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Flashcards in Endocrinology - Adrenals Deck (73):
1

What are the three zones of the adrenal cortex?

The adrenal cortex consists of the zona glomerulosa, the source of aldosterone (mineralocorticoid), zona fasciculata, accounting for 75% of the adrenal cortex and producing corticosteroids (glucocorticoids) and zona reticularis a narrow juxtamedullary ring of cells producing sex steroids.

2

What are structure are the adrenal steroids synthesised from?

All the steroids of the adrenal cortex are synthesised from cholesterol and are chemical modifications of it.

Cholesterol, progesterone, the glucocorticoids and the mineralocorticoids are all 21 carbon steroids.

Androgens are 19 carbon steroids and oestrogens (produced primarily in the ovaries) are 18 carbon steroids.

3

What is the basis of the specialisation of different layers of the adrenal cortex to synthesise and secrete particular steroid hormones?

Different layers of the adrenal cortex contain different enzymes responsible for the chemical modification of cholesterol. For example, the zona reticularis primarily produces androgens becayse they contain the 17,20-lyase enzyme. On the other hand, the zona glomerulosa produces aldosterone because it contains aldosterone synthase.

4

Where does the cholesterol needed for steroid hormone synthesis come from?

Cholesterol is the precursor to ALL steroid hormones. Most of the cholesterol is provided to the adrenal cortex via the circulation, and small amounts are synthesised de novo within the adrenal cortical cells. Cholesterol circulates bound to low density lipoproteins (LDLs). There are receptors for these lipoproteins in the membranes of adrenocortical cells. The lipoprotein-cholesterol complex binds and is enters the cell by endocytosis. Once inside the cell, cholesterol is stored in cytoplasmic vesicles until needed for steroid hormone synthesis.

5

What do the enzymes that catalyse cholesterol into active steroid hormones need?

They require cytochrome P450 complex, molecular oxygen and NADPH which serves as a hydrogen donor for the reducing steps. A flavoprotein enzyme called adrenodoxin reductase and an iron containing protein called adrenodoxin are intermediaries in the transfer of hydrogen from NADPH to the cyt-P450 complex enzymes.

6

After cholesterol what do all steroid hormones get converted to?

The first step in each pathway is the conversion of cholesterol to pregnenolone, catalysed by cholesterol desmolase. Thus, all layers of the adrenal cortex contain cholesterol desmolase. Cholesterol desmolase is the rate limiting enzyme in the pathway and is stimulated by ACTH.

7

What is the major glucocorticoid produced by the zona fasciculata of the adrenal cortex?

The major glucocorticoid in produced in humans is cortisol (hydrocortisone). Thus, zona fasciculata contains all the enzymes required to convert cholesterol to cortisol. These are:

1) cholesterol desmolase: converts cholesterol to pregnenolone
2) 17 alpha hydroxylase: which hydroxylates pregnenalone into 17-hydroxypregnenolone
3) 3 beta hydroxysteroid dehydrogenase: which converts 17-hydroxypregnenolone to 17-hydroxyprogesterone
4) 21 beta hydroxylase and 11 beta hydroxylase which hydroxylate C11 and C21 residues to produce the final product, cortisol

Interestingly, these do not have to happen in this exact order. For example, hydroxylation at C17 can occur before or after the action of 3 beta hydroxysteroid dehydrogenase.

8

Other than cortisol, what other steroid in the pathway has glucocorticoid activity? Why is this important?

Corticosterone also has glucocorticoid activity. If the 17 alpha hydroxylase step is blocked, the zona fasciculata can still produce corticosterone without any deleterious effects. Thus, cortisol is NOT absolutely necessary for life provided corticosterone is being produced.

However, blocks at the cholesterol desmolase, 3 beta hydroxysteroid dehydrogenase, 21 beta hydroxylase or 11 beta hydroxylase steps are devastating because they prevent the production of cortisol and corticosterone. In these cases, death will ensue without appropriate hormone replacement therapy.

9

What drugs significantly interfere with glucocorticoid biosynthesis?

Metyrapone and ketoconazole. Metyrapone inhibits 11 beta hydroxylase activity, the last step in cortisol synthesis. Ketoconazole inhibits several steps in the pathway including cholesterol desmolase, the first step.

10

What are the main androgens produced by the adrenal cortex?

DHEA and androstenedione are androgenic steroids produced by the zona reticularis. These compounds have weak androgenic activity, but in the testes are converted to testosterone, a more potent androgen. The precursors of adrenal androgens are 17 hydroxypregnenolone and 17 hydroxyprogesterone which are converted to androgens by the removal of the C20, 21 side chains.

In men, adrenal androgens are of little significance as the testes produce their own testosterone from cholesterol and do not require the adrenal precursors. In females, however, the adrenal cortex is a major source of androgenic compounds.

The zona reticularis also produces a very small amount of testosterone and 17 beta oestradiol, although the main sources for these hormones are the testes and ovaries respectively.

11

What is meant by the term 17-ketosteroids?

Adrenal androgens have a ketone group at C17 that distinguishes them from cortisol, aldosterone and testosterone. Thus, tha major adrenal androgens are called 17 ketosteroids which can be measured in the urine.

12

What is the major mineralocorticoid produced by the zona glomerulosa of the adrenal cortex?

The major mineralocorticoid in the body is aldosterone, which is synthesised ONLY by the zona glomerulosa. The steps required to convert cholesterol to corticosterone are identical to those in zona fasciculata and the addition of aldosterone synthase in the zona glomerulosa converts corticosterone to aldosterone.

13

Why does the zona glomerulosa not produce corticosteroids?

There are 2 reasons for this:
i) corticosterone, a glucocorticoid, is converted to aldosterone because this zone contains aldosterone synthase, and
ii) the zona glomerulosa lacks 17 alpha hydroxylase and therefore is unable to produce cortisol from progesterone

14

Is aldosterone the only steroid with mineralocorticoid activity?

No. 11-deoxycorticosterone (DOC) and corticosterone also have mineralocorticoid activity. Thus, if the mineralocorticoid pathway is blocked BELOW the level of DOC (e.g. absence of 11 beta hydroxylase or aldosterone synthase) mineralocorticoids will continue to be produced. However, if the pathway is blocked ABOVE the level of DOC (e.g. absence of 21 beta hydroxylase) then no mineralocorticoids will be produced.

15

Differentiate Cushing's syndrome from Cushing's disease

Cushing's syndrome refers to hypercortisolaemia and its associated signs and symptoms from ANY cause.

Cushing's disease refers specifically to hypercortisolaemia due to ACTH production by a pituitary adenoma.

The most common cause of Cushing's syndrome is iatrogenic, owing to exogenous steroid use to treat a number of conditions. If one excludes iatrogenic hypercortisolaemia, the most common cause of Cushing's syndrome is Cushing's disease, which accounts for approximately 2/3's of all cases.

16

What are the signs and symptoms of Cushing's disease?

Atrophic, thin skin; easy bruising and purple striae on abdomen, axilla, hips, and thighs

Weight gain or central obesity

Dorsocervical (buffalo hump) and supraclavicular fat accumulation

Moon facies

Menstrual irregularities

Hirsutism

Diabetes or insulin resistance

Muscle weakness

Hypertension

Increased susceptibility to infection

Frequent fungal infections

Osteoporosis or osteopenia

Psychiatric symptom such as depression, mood changes, and even psychosis

Hypercoagulable state

17

List the four steps involved in diagnosing Cushing's syndrome

Step 1: screen for and document hypercortisolaemia with a 24 hour urine cortisol or dexamethasone suppression test (DST)

Step 2: differentiate between ACTH dependent and ACTH independent causes by measuring ACTH

Step 3: distinguish pituitary Cushing's disease from ectopic ACTH secretion with a pituitary MRI and/or inferior petrosal sinus sampling (IPSS)

Step 4: surgically resect the tumour once identified

18

When should one screen for Cushing's syndrome?

The main indication is the in the presence of multiple symptoms of Cushing's syndrome or worsening features of Cushing's. However, the symptoms that could be associated with Cushing's syndrome - e.g. depression, weight gain, hypertension, diabetes, osteoporosis - are common. Consider screening adults with weight gain, an abnormal fat distribution, proximal muscle weakness, large purple striae and new cognitive depression.

In young people, be suspicious if there is non traumatic fractures, cutaneous atrophy or hypertension.

19

How should one screen for Cushing's syndrome?

The first line test of choice is the low dose (1 mg) overnight dexamethasone suppression test (DST).

24 hour urine free cortisol levels or late night salivary cortisol levels can also be undertaken.

20

How is the DST performed?

1mg of dexamethasone is given at 11pm and the serum cortisol is measured at 8am the following morning. If the patient does not have Cushing's, the 8am cortisol is suppressed (due to negative feedback on the pituitary) to <1.8ug/dL.

21

How is the 24 hour urine free cortisol done?

By collecting urine over 24 hours to measure free cortisol. To ensure an accurate result, the urine collection should be confirmed with a complete and simultaneous urine creatinine excretion. Urinary cortisol should be normal in patients without Cushing's syndrome. This test should be repeated if there is a normal first result but a high index of suspicion.

22

What is the late night salivary cortisol test?

Measurement of cortisol levels in salivary samples collected late at night. Some clinicians advocate this test because it is easy to perform and the salivary and plasma cortisol levels closely correlate. Normal cortisol levels should be low at night, confirming normal diurnal variation.

Cushing's patients have abnormally high late night levels. This test is more useful for patients who have episodic hypercortisolaemia, with most clinicians favouring the DST or 24 hour urine free cortisol.

23

What second line tests can be used if the DST or 24 urinary free cortisol is normal?

1) 48h dexamethasone suppression test: give dexamethasone 0.5mg/6h PO for 2d. Measure cortisol at 0 and 48h. Again in Cushing's syndrome there is a failure to suppress cortisol

2) 48h high dose dexamethasone suppression test: 2mg/6h may distinguish pituitary (suppression) from other causes (no/part suppression)

3) Midnight cortisol

24

Once hypercortisolaemia is confirmed what is the next step in evaluating a patient with Cushing's syndrome?

After ruling out ingestion of exogenous steroids, the next step is to differentiate between an ACTH dependent (80%) and an ACTH independent (20%) disease. ACTH dependent diseases are associated with pituitary adenoma (80%), ectopic ACTH (20%) and CRH hypersecretion (rare). ACTH independent disease is associated with adrenal adenoma, adrenal carcinoma, nodular dysplasia and McCune-Albright syndrome (rare).

Measurement of ACTH and cortisol. If ACTH >10pg/mL, the patient most likely has an ACTH dependent cause of Cushing's syndrome. In addition, an ACTH >10pg/mL after corticotrophin releasing hormone (CRH) administration suggests ACTH dependency (specifically due to a pituitary cause as cortisol rises with pituitary disease but not with ectopic ACTH).

25

If ACTH is undetectable how should the patient be investigated?

In this instance the likely cause is an adrenal tumour. A CT of the adrenal glands is the next step. If no mass is located then proceed to adrenal vein sampling or adrenal scintigraphy (radiolabelled cholesterol derivative).

26

Once ACTH-dependent Cushing's syndrome has been confirmed, what is the final step in making the biochemical diagnosis?

A high-dose (8-mg) DST or CRH test to differentiate between a corticotrope adenoma and an ectopic ACTH-secreting tumor. Patients with a pituitary source of ACTH retain suppressibility of cortisol to high-dose dexamethasone, whereas patients with ectopic ACTH tumors do not (because the tumour is autonomous).

Cortisol rises with pituitary disease following CRH administration, whereas it remains the same with ectopic disease.

27

How is the dexamethasone test confirmed?

If tests indicate that cortisol responds to manipulation, Cushing's disease is likely. Image the pituitary (MRI) and consider IPSS. This test takes advantage of the concentration gradient between pituitary venous drainage via the inferior petrosal sinus (IPSS) and peripheral venous values of ACTH to further determine whether an ACTH producing corticotropic adenoma is present in the pituitary. The inclusion of CRH adds greater sensitivity to the test.

28

Explain how IPSS is performed?

Samples of ACTH and cortisol are obtained simultaneously from the IPS (central) and from a peripheral site (e.g., inferior vena cava [IVC]). In patients with Cushing's disease, the central/peripheral ratio (C/P = IPS/IVC ratio) of ACTH > 2. In patients with ectopic ACTH, the ratio < 2 and selective venous sampling (e.g., of the pulmonary, pancreatic, or intestinal beds) may localize the ectopic tumor.

29

What is pseudo Cushing's?

A clinical state characterized by mild overactivity of the hypothalamic-pituitary-adrenal axis that is not associated with true Cushing's syndrome (hypercortisolemia) typically seen in a variety of psychiatric states (depression, anxiety), alcoholism, uncontrolled diabetes, and severe obesity. The dexamethasone-CRH stimulation test can be used to help distinguish this disorder from true Cushing's syndrome. Alternatively, an elevated midnight plasma cortisol level rules out pseudo-Cushing's because, unlike patients with true Cushing's syndrome, patients with pseudo-Cushing's retain the diurnal rhythm of cortisol secretion.

30

What is Nelson's syndrome?

Symptoms of a mass effect of corticotrope hyperplasia or adenoma in patients after bilateral adrenalectomy. Nelson's syndrome occurs in up to 30% of patients after bilateral adrenalectomy and patients often present with headache, visual field deficits, ophthalmoplegia, and hyperpigmentation owing to high levels of ACTH (with resultant high levels of melanocyte-stimulating hormone). Pituitary tumor resection followed by pituitary radiation can prevent Nelson's in someone who has had bilateral adrenalectomy.

31

Name some ectopic sources of ACTH?

Small cell lung cancer and thyroid carcinoid tumours.

Specific features are pigmentation (due to increased ACTH), hypokalaemic metabolic alkalosis (increased cortisol leads to mineralocorticoid activity), weight loss, hyperglycaemia. Classical features of Cushing's are often absent. Dexamethasone even in high doses fails to suppress cortisol production.

32

How is Cushing's treated?

This largely depends on the cause:
1) Iatrogenic - stop medications if possible

2) Cushing's disease - selective removal of pituitary adenoma, bilateral adrenalectomy if source unlocatable or recurrence post op (complication: Nelsons syndrome)

3) Adrenal adenoma or carcinoma - adrenalectomy "cures" adenamoas but rarely stops cancer. Radiotherapy and adrenolytic drugs (mitotine) follow if carcinoma

4) Ectopic ACTH - surgery if tumour is located and hasn't spread. Metyrapone, ketoconazole and fluconazole decrease cortisol secretion pre op or if waiting effects of radiation.

33

What is adrenal insufficiency?

Insufficient release of adrenal hormone, typically from the adrenal cortex involving both cortisol and aldosterone.

Note - anyone on exogenous steroids for long enough to suppress the pituitary adrenal axis or who has overwhelming sepsis or has metastatic cancer may suddenly develop insufficiency with deadly hypovolaemic shock.

34

What causes adrenal insufficiency?

The causes can be divided into two categories: primary and central. Primary adrenal insufficiency (Addison's disease) is due to adrenal gland dysfunction. Central adrenal insufficiency includes both secondary (pituitary) and tertiary (hypothalamic) causes.

35

List the causes of primary adrenal insufficiency.

Autoimmune destruction (70–80%), tuberculosis (20%), adrenal destruction by bilateral hemorrhage or infarction (e.g. Waterhouse-Friderichsen), tumor, infections (other than tuberculosis), surgery, radiation, drugs, amyloidosis, sarcoidosis, hyporesponsiveness to ACTH, and congenital abnormalities.

36

List the causes of central adrenal insufficiency.

Withdrawal of exogenous steroids (common), treatment and cure of Cushing's syndrome, pituitary adenoma/infarction, other causes of panhypopituitarism, pituitary or brain irradiation, and hypothalamic abnormalities (rare).

37

What are the signs and symptoms of Addison's disease?

Symptoms:
Weakness, fatigue
Anorexia, weight loss
Dizziness
GI upset: nausea, vomiting, diarrhoea
Abdominal pain
Salt craving

Signs:
Hyperkalaemia
Hyponatraemia
Orthostatic hypotension
Hyperpigmentation (buccal mucosa, skinfolds, extensor surfaces)
Vitiligo
Adrenal calcifications

38

How do Addison's disease and central adrenal insufficiency differ in their presentation?

Primary adrenal insufficiency (Addison's disease) is caused by failure or destruction of the adrenal glands, leading to underproduction of glucocorticoids and mineralocorticoids and an increase in ACTH production by the pituitary. Central adrenal insufficiency is caused by deficient production of ACTH, leading to underproduction of glucocorticoids. The manifestations are the same as those of Addison's disease with the following exceptions:

- Hyperpigmentation is not seen in central disease. Patients do not have hypersecretion of melanocyte-stimulating hormone (a product of the propiomelanocortin gene, like ACTH) that is responsible for the hyperpigmentation.

- Electrolyte abnormalities (hyponatremia, hyperkalemia) are not typically present in central disease because the aldosterone system is largely intact.

- Central disease may involve other manifestations of hypopituitarism.

- Hypoglycemia is more commonly seen with central disease owing to the presence of combined ACTH and GH deficiency.

39

What test do most clinicians use to assess adrenal insufficiency?

An ACTH stimulation test. In the classic test, a baseline cortisol is drawn and 250 μg of IV synthetic ACTH (Synacthen) is given. Blood samples for cortisol are collected at 30 and 60 minutes. A normal response is a stimulated cortisol value of > 18 μg/dL. A normal response rules out primary adrenal insufficiency. Patients with acute central adrenal insufficiency (i.e., pituitary apoplexy or head trauma) may respond to synthetic ACTH because the adrenal glands have not had sufficient time to become atrophic and unresponsive to ACTH. Lack of a normal response indicates decreased adrenal reserve but does not differentiate between primary and central adrenal insufficiency.

40

How do you distinguish between primary and central adrenal insufficiency?

By ACTH level. This level is high in primary adrenal insufficiency and low or normal in central. More recently, clinicians have considered the 250-μg ACTH test less accurate in detecting patients with mild secondary adrenal insufficiency (because it is a supraphysiologic dose) and have recommended a 1-μg ACTH stimulation test. The test is performed the same way as the higher-dose test but requires dilution of the ACTH. ACTH (Synacthen) is available only in a 250-μg vial and must be diluted for this low-dose test. Therefore, careful attention must be given to ensure proper administration of the drug to avoid a high false-positive rate.

41

Other than a short Synacthen test what other investigations are useful in adrenal insufficiency?

Na+ and K+ (due to decreased mineralocorticoid secretion), decreased glucose (due to decreased cortisol).

21 hydroxylase adrenal autoantibodies positive in autoimmune disease in >80%.

Plasma renin and aldosterone to assess mineralocorticoid status.

AXR/ CXR - any past TB, e.g. upper zone fibrosis or adrenal calcification

42

How is Addison's disease managed?

Replace steroids - 15-25mg hydrocortisone daily in 2-3 doses, e.g. 10mg on waking, 5mg at lunchtime. Avoid giving late (causes insomnia)

Mineralocorticoids to correct postural hypotension, Na+ and K+ - fludrocortisone PO

Steroid use! Warn against abruptly stopping. Give steroid card, advise wearing a bracelet. Add 5-10mg hydrocortisone to daily intake before strenuous activity/ exercise. Double steroids in febrile illness, injury or stress. Give out syringes and in date IM hydrocortisone and show how to inject 100mg IM if vomiting prevents oral intake.

43

What follow up is required for patients with Addisons disease?

Yearly BP and U+E's
Watch for autoimmune conditions (pernicious anaemia)

44

What is the gold standard test to assess adequacy of the HPA axis?

The insulin tolerance test (ITT). The principle of the test is to induce hypoglycemia (plasma glucose < 40 mg/dL) with IV insulin, which acts as a major stressor to stimulate production of ACTH, cortisol, and GH. The ITT can be dangerous and requires close monitoring.

45

What are other tests that can be used to diagnose central adrenal insufficiency?

Besides the ITT, metyrapone can be given at 11 pm to suppress cortisol synthesis. If the pituitary adrenal axis is intact, morning measurements of ACTH and 11-deoxycortisol, the precursor to cortisol, will rise to > 75 pg/mL and 7 μg/dL, respectively, if there is no secondary adrenal insufficiency. Metyrapone is not commercially available but can be obtained by contacting the manufacturer, Novartis Pharmaceuticals.

46

Why is it important to rule out adrenal insufficiency in pituitary patients with central hypothyroidism?

Because patients with central hypothyroidism metabolize cortisol more slowly than euthyroid patients. Thyroid hormone replacement increases cortisol metabolism and can precipitate adrenal crisis in a patient with undiagnosed central adrenal insufficiency. Adrenal insufficiency should be detected and treated before starting thyroid hormone replacement.

47

What is primary hyperaldosteronism?

Excessive production of aldosterone independent of the renin-angiotensin system, found in approximately 0.5–2% of the population. The differential diagnosis includes solitary aldosterone-producing adenoma (Conn's syndrome) (65%), bilateral or unilateral adrenal hyperplasia, adrenal carcinoma, and glucocorticoid-remediable aldosteronism.

48

How do patients with primary hyperaldosteronism present?

With hypertension, hypokalemia (weakness, muscle cramping, paresthesias, headaches), low magnesium levels, and metabolic alkalosis.

There is also raised plasma aldosterone with, in Conn's syndrome, suppressed plasma renin.

49

How should patients with primary hyperaldosteronism be evaluated initially?

With a morning ambulatory plasma aldosterone level and PRA in the absence of drugs that alter the renin-aldosterone axis (spironolactone, eplerenone or high-dose amiloride). A ratio of plasma aldosterone concentration to plasma renin activity ratio of ≥20 and a plasma aldosterone concentration of ≥15 ng per deciliter makes the diagnosis of hyperaldosteronism likely.

50

How is the diagnosis of primary hyperaldosteronism confirmed?

With a high 24-hour urine aldosterone level in the presence of normokalemia and adequate volume status or inadequate suppression of aldosterone levels using the saline suppression or salt-loading test. As always, biochemical diagnosis should precede diagnostic imaging. Treatment depends on the etiology but usually includes surgery except in cases of adrenal hyperplasia or glucocorticoid-remediable hyperaldosteronism. Renal vein sampling can lateralize the aldosterone source before surgery.

51

How are patients with primary hyperaldosteronism treated?

If Conn's then treatment is usually surgical with a laparoscopic adrenalectomy. Spironolactone for 4 wks pre op controls BP and K+.

Hyperplasia on the other hand is treated medically with spironolactone, amiloride or eplerenone (a new selective aldosterone receptor antagonists which doesn't cause gynaecomastia).

GRA is glucocorticoid remediable aldosteronism and is a rare cause of primary hyperaldosteronism. Genetic testing can be used to confirm the diagnosis but dexamethasone 1mg/24h PO for 4 wks is the treatment of choice. It usually normalises biochemistry but not BP. If BP is still raised then use psironolactone as an alternative

Adrenal carcinoma is treated with surgery followied by post operative adrenolytic therapy with mitotane - prognosis is poor.

52

What is secondary hyperaldosteronism?

This is caused by high renin release from reduced renal perfusion - e.g. in renal artery stenosis, accelerated hypertension, diuretics, CCF or hepatic failure.

Renin secreting tumours are exceptionally rare.

53

What is Bartter's syndrome?

This is a major cause of congenital (autosomal recessive) salt wasting - via a sodium and chloride leak in the loop of Henle via a defective channel. It presents in childhood with failure to thrive, polyuria, and polydipsia. BP is normal. Sodium loss leads to volume depletion causing increased renin and aldosterone production leading to hypokalaemia and metabolic acidosis, raised urinary K+ and Cl-. Treatment is usually with K+ replacement, NSAIDS to inhibit prostaglandin and ACEi.

54

What is the gold standard test to assess adequacy of the hypothalamic-pituitary-adrenal axis?

The insulin tolerance test (ITT). The principle of the test is to induce hypoglycemia (plasma glucose < 40 mg/dL) with IV insulin, which acts as a major stressor to stimulate production of ACTH, cortisol, and GH. The ITT can be dangerous and requires close monitoring.

55

What are other tests that can be used to diagnose central adrenal insufficiency?

Besides the ITT, metyrapone can be given at 11 pm to suppress cortisol synthesis. If the pituitary adrenal axis is intact, morning measurements of ACTH and 11-deoxycortisol, the precursor to cortisol, will rise to > 75 pg/mL and 7 μg/dL, respectively, if there is no secondary adrenal insufficiency.

56

Why is it important to rule out adrenal insufficiency in pituitary patients with central hypothyroidism?

Because patients with central hypothyroidism metabolize cortisol more slowly than euthyroid patients. Thyroid hormone replacement increases cortisol metabolism and can precipitate adrenal crisis in a patient with undiagnosed central adrenal insufficiency. Adrenal insufficiency should be detected and treated before starting thyroid hormone replacement.

57

What is a phaeochromocytoma?

This is a rare catecholamine producing tumour that arises from sympathetic paraganglia cells which are collections of chromaffin cells. They are usually found within the adrenal medulla. Extra-adrenal tumours (paragangliomas) are rarer and often found by the aortic bifurcation (the organs of Zuckerkandl).

58

What is the "classic triad" of symptoms associated with phaeochromocytoma?

Episodic headache, diaphoresis, and tachycardia with or without hypertension. The hypertension may be paroxysmal. Other symptoms may include anxiety/psychiatric disturbances, tremor, pallor, visual changes (papilledema, blurred vision), weight loss, polyuria, polydipsia, hyperglycemia, dilated cardiomyopathy, and arrhythmias. Most patients have two of the three symptoms of the classic triad. If the patient is hypertensive and has the classic triad of symptoms, the sensitivity and specificity for pheochromocytoma are both > 90%.

59

What other diagnoses should be considered in the diagnosis of pheochromocytoma?

Anxiety/panic attacks, alcoholism (or alcohol withdrawal), sympathomimetic drugs (cocaine, amphetamines, phencyclidine, epinephrine, phenylephrine, terbutaline, and phenylpropanolamine [a popular over-the-counter decongestant]), combined ingestion of MAO inhibitor and tyramine-containing food, hyperthyroidism, menopause, hypoglycemia, and abrupt discontinuation of short-acting sympathetic antagonists (e.g., clonidine).

60

What is the “rule of 10” for pheochromocytomas?

10% are extra-adrenal

10% are bilateral

10% are familial

10% are malignant

61

How do you evaluate a patient with suspected pheochromocytoma?

By making a biochemical diagnosis before embarking on radiographic imaging. Confirming the presence of excess catecholamines is crucial because people can have incidental adrenal tumors that do not hypersecrete catecholamines.

62

Describe the main screening tests for pheochromocytoma.

Although preferences may vary by institution, 24-hour urine catecholamines and metanephrines measurements are available in most laboratories. Plasma-free normetanephrine and metanephrine levels are also useful but not readily available. If these values are more than two- to fourfold higher than the upper limit of the normal reference range, proceed to abdominal CT scan or MRI to localize the tumor.

63

What other tests may be helpful?

Clonidine suppression test, chromagranin A, and neuropeptide Y.

64

Under what conditions is the 24-hour urine test performed?

Usually when the patient is symptomatic because catecholamine hypersecretion may be episodic. If possible, testing should be performed after discontinuing medications. TCAs and antipsychotics are most likely to interfere with the measurement. Caffeine, alcohol, acetaminophen, decongestants, and tobacco should be avoided during testing. Cocaine, appetite suppression drugs, and other sympathomimetics should also be discontinued.

65

Describe the clonidine suppression test.

Plasma catecholamines are measured before and 3 hours after oral administration of 0.3 mg of clonidine. Failure to suppress plasma catecholamines suggests the diagnosis of pheochromocytoma. This test must not be performed in hypovolemic patients or patients taking diuretics, beta blockers, or TCAs.

66

After the biochemical diagnosis is made, how is the tumor localized?

By using CT or MRI (first of the adrenals, then of the chest, abdomen, and pelvis). If the tumor cannot be localized with standard imaging, perform an 123l metaiodobenzylguanidine (MIBG) scan to localize functional catecholamine-rich tissue.

67

What is the treatment of choice for patients with pheochromocytomas?

Surgery after the tumor is localized. All patients must be preoperatively treated with alpha adrenergic (phenoxybenzamine) and beta adrenergic (atenolol) blockade to avoid stress-induced catecholamine excess and hypertensive crisis during surgery. Dose should be titrated to cause orthostatic hypotension. If only beta adrenergic blockade is provided, the patient may develop peripheral vasoconstriction and an exacerbation of hypertension.

68

How common are cortical adenomas? Describe their appearance

Cortical adenomas are extremely common, and are an incidental finding in up to 30% of post mortem cases.

Macroscopically, they appear as small, encapsulated, yellow nodules which are unilateral or bilateral, single or multiple.

Microscopically, the adenomas resemble the normal cortex although the zonal arrangements may be disorderly.

69

What are the effects of cortical adenomas?

1) Inactive - the vast majority have no clinical effects
2) Functional - these tumours are usually larger;
(a) Cushing's syndrome;
(b) Conn's syndrome;
(c) virilization or feminisation

70

How common are cortical carcinomas?

These are rare tumours, and can affect all ages. But in children functional cortical carcinoma is the commonest cause of Cushing's syndrome.

71

Describe the appearance of cortical carcinomas?

Macroscopically, they appear as globular, large, soft lobulated, yellow tumours with a soft, haemorrhagic and necrotic cut surface. Adjacent organs, particularly the kidneys are commonly invaded. The tumour is bilateral in 10%.

Microscopically, the tumours appearance is very variable. Some tumours show close resemblance to normal cortical cells, whilst others are anaplastic type containing bizarre giant cells. The best guide to the malignancy of a functioning adrenal tumour its its size.

72

What are the effects of adrenal cortical carcinoma?

1) Endocrine
(a) inactive - the tumours have no functional activity
(b) functional - Cushing's syndrome, often with particularly marked tendency to virilization in females

2) Local - there is normally a large mass with invasion of neighbouring organs

73

How does adrenal cortical carcinoma spread?

1) Direct - kidney, posterior abdominal wall, diaphragm, liver, spleen

2) Lymphatic - invaded regional lymph nodes are commonly seen by the time of diagnosis

3) Blood - spread to the other adrenal gland is common, as are metastases to the lungs, bone and brain

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