Pathology of the Adrenal Gland and Endocrine Pancreas

Question 1

Identify the main conditions involving Adrenal hyperfunction.

Answer 1

• Cushing’s syndrome
• Conn’s syndrome
• Adrenogenital syndrome and congenital adrenal hyperplasia
• Adrenocortical neoplasms

Question 2

What is the underlying problem in Cushing’s syndrome ? Identify its main clinical features.

Answer 2

Excessive secretion of cortisone (also mineralocorticoid effects).

CLINICAL FEATURES
• Muscle wasting (due to muscle catabolism)
• Fat (including abnormal distribution causing moon face and buffalo hump, due to increased insulin release)
• Impaired glucose tolerance (due to B-cell exhaustion, which is due to increased insulin release)
• Hyperglycaemia (due to gluconeogenesis in liver- adrenal/steroid diabetes)
• Abnormal collagen maturation (causing striae)
• Tissue edema, Hypertension and hypoK (Due to increased glomerular filtration (glucocorticoid effect) and water and Na+ retention (mineralocorticoid effects))
• Osteporosis
• Hirsutism
• Depression/psychosis
• GI tract ulceration (due to excess H+ secretion and decreased mucous production (alkalosis due to increased H+ loss in GI tract and kidney))
• Immunosuppressive and anti-allergic and anti-inflammatory actions (decreases in protein synthesis results in increased neural excitability, lymph node lysis, inhibition of haematopoiesis and lymphocyte production)
——
(also increase in FFA in plasma due to reduced lipogenesis and enhanced lipolysis)

Question 3

Distinguish between primary and secondary adrenal problems causing Cushing’s.

Answer 3

Primary is due to primary adrenal problem, where secondary is due to exogenous causes (e.g. medications, surgery)

Question 4

Describe the epidemiology of Cushing’s.

Answer 4

Female > Male

Question 5

What are the main causes of Cushing’s ? Rank these by decreasing frequency.

Answer 5

From most to least frequent causes:

1) Pituitary Adenoma producing ACTH (resulting in adrenal hyperplasia and no working feedback system)
2) Primary adrenal neoplasm (50:50 between benign and malignant)

3) Ectopic ACTH (i.e. “from non-pituitary tumors” e.g. Small cell lung carcinoma or Bronchial carcinoid tumors)
or related peptides leading to adrenal hyperplasia (paraneoplastic syndromes)

4) Iatrogenic leading to adrenal atrophy

Question 6

Do most adrenal neoplasms produce excess steroids ?

Answer 6

No, most adrenal neoplasms do NOT produce excess steroids (be they benign or malignant).

Question 7

How is Cushing’s Syndrome managed ?

Answer 7

Treat underlying cause (e.g. if tumor, then can surgically remove but may then end up with no ACTH, so may also need replacement therapy. e.g. decreases in drug dosage if due to excess corticosteroids)

Question 8

What is another name of primary hyperaldosteronism ? What are potential causes of it ?

Answer 8

Conn’s syndrome

CAUSES:

• Adrenal adenoma (80%)
• Idiopathic Adrenal hyperplasia (bilateral adrenal hyperplasia of zona glomerulosa, adrenal cells become hyperplastic, resulting in excess secretion of aldosterone)
• Adrenal carcinoma (rare)

Primary is NOT driven by renin

Question 9

What are the main biochemical features of Conn’s ? Link these to clinical features of it.

Answer 9

• Hypokalaemia (related to muscle weakness and cramps)
• Metabolic alkalosis (can predispose patients to cardiac arrhythmias)
• High aldosterone (reabsorbing sodium and excreting potassium)
• Low renin

Question 10

Describe epidemiology of Conn’s.

Answer 10

Females > males 4:1

Question 11

How is Conn’s managed ?

Answer 11

Depends on the cause:

Adrenal adenoma, resect

Bilateral hyperplasia, surgery or BP control

Question 12

What is secondary hyperaldosteronism ?

Answer 12

Increased renin-angiotensin activity eg as a result of renal ischaemia (e.g. due to renal artery stenosis)

Question 13

Identify the main genetic defects involved in congenital adrenal hyperplasia.

Answer 13

• 21 hydroxylase deficiency (CYP21), so non-hydroxylated versions of cortisol, corticosterone and aldosterone are made, which lack normal activity and do not negatively feedback on the HPA axis. Hence, high levels of ACTH cause constant stimulation of production of C-19 androgens. This leads to genital changes and early puberty (due to increased androgens) in addition to other health problems related to decreased cortisol and aldosterone).
• 11-beta hydroxylase deficiency

These are both enzymes involved in biosynthesis of steroids.

Question 14

Identify the main adrenal neoplasms.

Answer 14

BENIGN

MALIGNANT

• Primary (affecting cortex, and medulla)
• Secondary (COMMON, most commonly from lung, breast, and kidney, latter may be directly infiltrating)

Question 15

Identify the clinical features of secondary adrenal tumors.

Answer 15

Usually do not produce clinical sequelae (because two adrenals so if only one involved, have some normal adrenal uninvolved). If it does manifest, will manifest in late disease

Question 16

How are adrenal adenomas diagnosed ?

Answer 16

ONLY diagnosed in life if functional (most of them are NOT functional (i.e. not producing steroids) and NOT invasive)

Question 17

How are adrenal adenomas treated ?

Answer 17

• Low malignant potential so treat conservatively

Question 18

Describe prognosis, clinical features, and management of adrenal carcinomas.

Answer 18

Poor outlook (because often present late + site is difficult to access + easily spreads into adjacent structures + aggressive)

Clinical features related to the fact that more often secrete sex steroids (e.g. hirsutism, amenorrhea)

Management: chemo, radio, immunotherapy not effective, surgical removal can be an option

Question 19

What is the use of identifying molecular changes in the context of adrenal neoplasms ?

Answer 19

1. possible use in distinguishing adenoma from carcinoma – limited use
2. identification of familial syndromes

Question 20

Identify molecular changes in carcinoma.

Answer 20

• Proliferation markers increased
• Mutant p53 protein increased
• IGF II increased
• EGFR increased

Question 21

Identify genes which can help identify familial syndromes.

Answer 21

• p53
• MEN1 (patients with this mutations inherited it, so may be vulnerable to other endocrine tumor, and other family members may also be vulnerable)

Question 22

Identify an adrenal tumor arising from adrenal medulla.

Answer 22

-Phaeochromocytoma (Chromaffin cells)

Question 23

What are the main clinical features of Phaeochromocytoma ? Explain why they occur.

Answer 23

• Intermittent production of catecholamines causes:

• Hypertension
• Sweating
• collapse
• Glycosuria

BUT these features are not present all the time, due to the intermittent nature of catecholamine production (may only appear in times of stress, i.e. episodic symptoms)

Question 24

Describe genetic basis, and malignancy potential of Phaeochromocytomas.

Answer 24

• 20% are familial (may be part of MEN) but MOST are spontaneous (sporadic, so unilateral)
• Spectrum of benign (most of them, can be resected) to frankly malignant (10%) (aggressive chemo)

Question 25

Describe the cytological featuers of Phaeochromocytomas.

Answer 25

Histologically, difficult to distinguish between benign and malignant .

Question 26

Describe epidemiology, and prognosis of Neuroblastomas.

Answer 26

Affects young children

• N-mycamplification or adrenal site mean worse prognosis

Question 27

Identify causes of acute adrenal hypofunction.

Answer 27

• Disseminated intravascular coagulation causing infarct in adrenal cortex, often mediated by Meningococcal septicaemia (any sepsis can lead to DIC), resulting in loss of adrenal tissue and hence hypofunction

Question 28

Identify causes of chronic adrenal hypofunction.

Answer 28

Addison’s Disease associated with destruction of adrenal cortex (those cells are not repopulated))
AKA primary adrenal cortical insufficiency

Amyloid (can be deposited), TB (can get into adrenals), metastasis (usually no clinical features but occasionally may cause hypofunction)

Question 29

What are the main causes of Addison’s disease ?

Answer 29

• Autoimmune adrenalitis >75%
• Tuberculosis
• Amyloid
• Metastasis
• HIV - decreased immunity and increased viral and bacterial infections (that target the cortex)
• Atrophy due to prolonged steroid therapy

Question 30

Identify chronic conditions associated with Addison’s.

Answer 30

Patients with Addison’s may also have:

• Vitiligo
• Diabetes

Question 31

Identify the main clinical features of Addison’s.

Answer 31

Lack of catabolism + changes in Sodium result in:
• Lethargy
• Weakness
• Anorexia
• Pigmentation of skin and mucous membranes (due to rebound increase in ACTH, and melanocytes stimulating hormone is related to ACTH)
• Low plasma glucose esp. after fasting (lack of glucocorticoid actions)
• Low plasma Na+ (hyponatriemia) and high plasma K+ (hyperkalaemia) (due to lack of mineralocorticoids), associated with dehydration and hypotension including postural hypotension (systolic blood pressures 50-80 mmHg)

Question 32

What is the ratio of type 1 to type 2 DM ?

Answer 32

• DM2:DM1 ratio = 10:1

Question 33

Distinguish between epidemiology of DM type 1 and 2.

Answer 33

Type 1: Under 40, childhood, thin (because of catabolism partly)
Type 2: Over 40y, obese

Question 34

To what extent does DM type 1 have a genetic element ? DM type 2 ?

Answer 34

• Type 1: 40% concordance in
mono-zygotic twins (so strong genetic element)

• Type 2: No MHCII linkage

Question 35

Identify a possible complication of DM type 1.

Answer 35

DKA (prodromally may get decreased glucose as cells are destroyed and lose insulin, but then as lose insulin and cells, may become ketotic because no other energy source to burn, because cannot take up glucose)

Question 36

To what extent does ketosis occur in type 2 DM ?

Answer 36

• Hyperosmolar not ketosis

Question 37

Which of type 1 or 2 DM is associated with amyloid ? How so ?

Answer 37

Type 2:

May be associated with amyloid deposition due to production of amylin by beta cells which eventually forms amyloid

Question 38

Identify non-typical causes of diabetes.

Answer 38

1) Pancreatitis
- Acute
- Chronic, fibrosis compromise of beta cells, less insulin so insulin-dependent

2) Cystic Fibrosis
- Ducts become scarred and damaged, with fibrosis destroying exocrine pancreas
- Overtime, scarring also also destroy islets

3) Tumors
- If destructive (usually quite localized if in the pancreas, so remainder of pancreas still functions)

Question 39

What is the significance of endocrine tumors ?

Answer 39

They are functional + may be multiple + may be part of MEN syndrome + part of spectrum and many can have malignant potential

Question 40

Identify examples of endocrine neoplasms.

Answer 40

Insulinoma

Gastrinoma (too much gastrin, so too much HCl, so ulcers)