Endocrine Disease

Question 1

Endocrine System

Answer 1

Highly integrated and widely distributed group of organs that provide a system of communication and control in the body.

Uses chemical substances, hormones, to regulate and integrate body functions.

Metabolism, growth/development, tissue function, sexual function, reproduction, sleep, mood

Derived from the greek word “endo” for within, and “crinis” for secrete

Question 2

Endocrine

Answer 2

Release of hormone into bloodstream
Transport to target organ → action at distant site

Hormone -> bloodstream -> target organ -> action at distant site

Example: hypothalamic-pituitary-adrenal axis

Question 3

Exocrine

Answer 3

Secrete substance onto a surface by way of a duct

Example: salivary or sweat glands, GI tract, (pancreas - digestive enzymes)

Question 4

Paracrine

Answer 4

Secrete hormone that acts locally on adjacent cells

Example: estrogen on ovary

Question 5

Autocrine

Answer 5

Secrete hormone that acts on cells from which it was produced

Example: insulin inhibits release from pancreatic beta cells

Question 6

Negative Feedback system

Answer 6

Gland A → hormone A → bloodstream → act on gland B → hormone B → bloodstream → target organ AND inhibit secretion of gland A/hormone A

Question 7

Steroid hormones

Answer 7

(e.g. glucocorticoids, estrogen, progesterone)
5 points
Cholesterol backbone
Water insoluble (due to lipid content)
Carried in blood by carrier proteins
Can penetrate the PM in order to bind to cytosolic or nuclear receptors
Targeted gene expression changes

Ex.: Estrogen, progesterone, testosterone
Glucocorticoids, mineralocorticoids

Question 8

Protein and peptide hormones

Answer 8

Proteins: anterior pituitary hormones, e.g. adrenocorticotropic hormone [ACTH]
Peptides: antidiuretic hormone [ADH], growth hormone
Water soluble (polar molecules)
Transported freely in the blood
Cannot traverse the PM
(All three opposite to lipids)
They bind to receptors on the PM to activate second messenger signalling

Ex.: Hypothalamic releasing factors/hormones
CRH, TRH, GHRH, GIH (gonad-inhibiting hormone), GnRH
Anterior pituitary hormones
ACTH, TSH, GH, FSH, LH, PRL (prolactin)
Posterior pituitary hormones (neurohypophysis)
ADH, oxytocin

Question 9

Amino acids and amines

Answer 9

Amino acids: thyroxine
Amines: epinephrine
Modified/derived from amino acids (mostly tyrosine, also tryptophan)

Amine ex.: Thyroid hormones (T4, T3)
Catecholamines (epinephrine, norepinephrine)

Question 10

Endocrine system

Answer 10

Involves the hormone-producing organ, the hormone itself, and the receptor or target organ.
One hormone may act on more than one target organ.

Question 11

Classic and new definitions of endocrine system

Answer 11

Classically the endocrine hormone producing organs are ductless glands that secrete hormones directly into the bloodstream to be transported to, and exert their actions at, distant target organs (e.g. pituitary produces ACTH (corticotropin) that acts on the adrenal cortex), as opposed to the exocrine glands that secrete substances onto a surface of the body by way of a duct (e.g. sweat glands).

Definition of the Endocrine System has been widened now to include a more diverse group of cells in a wide variety of organs.

Some hormones never enter the bloodstream but instead act locally on adjacent cells; a paracrine action (e.g. estrogen acting on the ovary).
Hormones can also exert an autocrine action on the cell from which they were produced (e.g. insulin released from pancreatic β-cells can inhibit its release from the same cells).

Question 12

Endocrine glands

Answer 12

Hypothalamus, pituitary, pineal body (head)
Thyroid, parathyroid and thymus of the throat area
Adrenal glands sitting atop the kidneys
Pancreas near the stomach (the pancreas is an exocrine gland too, secreting bile into the bile duct and protein and fat-digesting enzymes into the pancreatic duct for emptying into the stomach)
Gonads (male testes and female ovaries).

Question 13

Endocrine pathology

Answer 13

All endocrinology can be divided into a problem of too much hormone, too little hormone or hormones acting at the wrong time.

Overproduction (hyperfunction)
Underproduction (hypofunction)
Nonfunctional receptors that cause target cells to become insensitive to hormones

Most endocrine diseases result from abnormalities in the producing organ.

Because the endocrine system is a ‘body’ control system relatively small lesions in one organ can produce widespread and important clinical consequences.

Several processes may disturb the normal activity of the endocrine system including:

Impaired synthesis or release of hormone
Abnormal interactions between hormones and their target tissues
Abnormal responses of target organs to their hormones

Question 14

Pituitary

Answer 14

The control centre of the endocrine system.

The pituitary itself is under the influence and control of the brain and thus, the two main body control systems, neural and endocrine, work in tandem.

The pituitary receives signals from the hypothalamus, a region of the brain that receives incoming pathways regarding sight, smell, temperature, hunger, rage, and fear.
In response to these signals it releases peptides called releasing factors or releasing hormones to a special group of blood vessels called the hypothalamohypophyseal portal system.

This specially designed system carries both stimulatory and inhibitory peptides to the anterior pituitary to affect specific groups of cells within this portion of the gland.
These cells then release hormones to specific target endocrine organs.

Hypothalamus signals -> pituitary -> releasing factors/releasing hormones -> hypothalamohypophyseal portal system -> anterior pituitary cells -> hormones -> target organs

Question 15

Levels of control of the endocrine system

Answer 15

Tertiary (hypothalamic)
Secondary (pituitary)
Primary endocrine organs (e.g. thyroid, adrenal, etc.).
Labelling is in reverse order relative to the pathway

Question 16

Control effect of cortisol

Answer 16

Inhibits CRH and ACTH

Question 17

Challenge of endocrinology

Answer 17

To determine what level of control is abnormal in a given patient, as abnormalities at each level share many, but not all, clinical features.

Question 18

Principal mode of internal control in the endocrine system

Answer 18

Negative feedback - product of the target organ turns off the control organ.

By measuring levels of both the final hormone and the hypothalamic and pituitary factors stimulating its production, an endocrinologist can often determine the site of abnormality.
In clinical practice such sophisticated and costly tests are often not necessary as symptoms, features on physical examination, or radiologic investigations can localize these lesions more cheaply and efficiently.

Question 19

Anterior pituitary hormones and control

Answer 19

Releases 6 hormones under the control of stimulatory (+) or inhibitory (-) hypothalamic releasing factors:

TRH → TSH, thyroid stimulating hormone
PIF inhibits PRL, prolactin
CRH → ACTH, adrenocorticotropic hormone (corticotropin)
GHRH → GH, growth hormone (inhibited by GIH)
GnRH → FSH, follicle stimulating hormone
GnRH → LH, luteinizing hormone

Question 20

Pituitary anatomy and function

Answer 20

Pituitary gland is a small, bean-shaped structure that sits at the base of the brain within the sella turcica.

“Master gland” under control of the hypothalamus

Connected to the hypothalamus physically and directly by a stalk composed of axons extending from the hypothalamus and indirectly through the rich venous plexus constituting the hypothalamo-hypophyseal portal system.

Question 21

Pituitary gland composition

Answer 21

Composed of two morphologically and functionally distinct components: the anterior pituitary or adenohypophysis and the posterior pituitary or neurohypophysis.

Question 22

Posterior lobe (neurohypophysis)

Answer 22

Composed of modified glial cells (pituicytes) and axonal processes extending from nerve cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus.

These hypothalamic neurons produce two peptide hormones, ADH or antidiuretic hormone, and oxytocin (the latter stimulates contraction of smooth muscle in the pregnant uterus and mammary glands).

ADH is released into the general circulation and acts on the collecting tubules of the kidney to promote the reabsorption of water.
ADH deficiency causes diabetes insipidus characterized by excessive urination (polyuria).

Question 23

Anterior lobe (adenophypophysis)

Answer 23

Composed of epithelial cells which in routine histological sections contain a variety of cells containing basophilic, eosinophilic, or poorly staining (chromophobic) cells.

The staining properties of these cells are related to the presence of various hormones within their cytoplasm; immunohistochemical stains are now used to identify specific hormone-producing cells.

Release of trophic hormones in the pituitary is under the control of factors produced in the hypothalamus.

Most of the hypothalamic factors are stimulatory except for dopamine (which inhibits prolactin secretion) and somatostatin (which inhibits growth hormone release).

Question 24

Symptoms of pituitary disease

Answer 24

Hyperpituitarism or excess secretion of hormones
Hypopituitarism or deficient secretion of hormones
Local effects (usually due to an increase in mass of a local lesion or presence of a tumor).

Question 25

Hyperpituitarism

Answer 25

Hyperpituitarism

Most common cause of hyperpituitarism is an adenoma arising in the anterior lobe.
Occur in both sexes at almost any age, but more common in men 20-50 years
These pituitary adenomas are classified on the basis of the hormone(s) produced by the neoplastic cells, which are detected by immunohistochemical staining tissue sections.

Usually consist of one cell type; hyperPRL most common (26%)
Occasionally two - most commonly GH and PRL

Question 26

Types of pituitary adenomas

Answer 26

Pituitary adenomas can be

Microadenomas (< 1 cm)
Macroadenomas (>1 cm)
Functional: effects associated with clinical manifestations of hormone excess
Silent: immunohistochemical demonstration of hormone production but no manifestations of hormone excess

As it increases in size, may disrupt normal pituitary function and lead to hypopituitarism

Most adenomas consist of one cell type and produce one hormone (e.g. prolactinoma, GH-producing adenoma, corticotroph adenoma).
Some pituitary adenomas can secrete two hormones, growth hormone and prolactin being the most common.

Question 27

Pituitary adenoma structure

Answer 27

The usual pituitary adenoma is a well-circumscribed, soft lesion confined by the sella turcica.
Microscopically pituitary adenomas are composed of relatively uniform, polygonal cells arrayed in sheets, cords, or papillae.
Supporting connective tissue, or reticulin, is sparse.
The nuclei of the neoplastic cells may be uniform or pleomorphic.
The cytoplasm may be acidophilic, basophilic, or chromophobic depending on the type and amount of secretory product within the cell and is fairly uniform throughout (cellular monomorphism).

Question 28

Prolactinoma

Answer 28

In women hyperprolactinemia causes amenorrhea, galactorrhea, and infertility
In men, libido and erectile dysfunction
Most common type of hyperfunctioning pituitary adenoma

Small microadenomas
Treated with dopamine agonists to inhibit PRL secretion

Large, expanding tumors associated with considerable local mass effects
Treated surgically or with radiation therapy

Prolactinomas are usually diagnosed at an earlier age in younger women in whom the clinical manifestations are more prominent than in men and older, postmenopausal women (e.g. amenorrhea).

Question 29

Hyperprolactinemia

Answer 29

Causes amenorrhea (absence of menstruation), galactorrhea (excessive or spontaneous flow of milk), loss of libido, and infertility.
Caused by other conditions (e.g. pregnancy, dopamine inhibiting drugs, hypothalamic lesions)
Hyperprolactinemia may be caused by pregnancy, high dose estrogen therapy, renal failure, hypothyroidism, hypothalamic lesions, and DA-inhibiting drugs.
Any mass in the suprasellar compartment may disturb the normal inhibitory effect of hypothalamic dopamine on prolactin secretion resulting in hyperprolactinemia (the stalk effect).

Thus, mild elevations in serum PRL in someone with a pituitary adenoma do not necessarily indicate a PRL-secreting neoplasm.

Question 30

Growth hormone (or somatotroph cell) adenomas

Answer 30

Second most common neoplasm.
In children - gigantism (growth plates have not fused)

In adults - acromegaly (growth plates have fused, no more growth in long bones)

Coarse facial features, overgrowth of mandible and maxilla, thickened nose
Hands and feet enlarge
Thickened calvarium (hat size increases)
Incidence of cardiovascular, cerebrovascular, and respiratory deaths increase (cardiomegaly, HTN, CHF)
Insulin resistance, abnormal glucose tolerance
Neurological and musculoskeletal symptoms (headaches, muscle weakness, paresthesia, arthritis, osteoporosis)

Question 31

Growth hormone adenoma composition

Answer 31

Composed of densely or sparsely granulated cells which stain immunohistochemically for GH.

If a GH-secreting tumor occurs in children before the epiphysis is closed in growing long bones then excessive levels of GH result in gigantism (a generalized increase in body size with disproportionately long arms and legs).
In adults elevated levels of GH produces acromegaly (growth in soft tissues, skin, bones of the face, hands and feet).

PRL is demonstrable in a number of GH-producing tumors and in some cases in sufficient quantities to produce signs of hyperprolactinemia.

Treatment:
Surgical removal of pituitary
GH antagonists
Radiotherapy

Question 32

Other anterior pituitary neoplasms

Answer 32

Corticotroph cell adenomas
Gonadotroph adenomas
Thyrotroph adenomas.
Pituitary carcinomas are exceedingly rare.

Question 33

Null cell adenomas

Answer 33

Silent and hormone-negative adenomas are more likely to come to attention at a later stage than those associated with endocrine abnormalities and hence, are more likely to be macroadenomas.

Do not stain for hormones (non functional)
Come to attention at a later date due to size and local mass effect

17% of adenomas

Question 34

Null cell adenoma presentation

Answer 34

Typical presentation is related to local mass effects including:

Radiologic abnormalities of the sella turcica (expansion, bony erosion, disruption of the diaphragma sellae)
Visual field abnormalities (e.g. bitemporal hemianopsia) due to expansion and compression of the optic nerve fibres in the optic chiasm
Elevated intracranial pressure
Seizures or obstructive hydrocephalus
Cranial nerve palsy (with involvement of the cranial nerves)

Compression of cranial nerves

Rarely, loss of consciousness and pituitary apoplexy (caused by acute hemorrhage into an adenoma)

Infarction causes both of these
Sudden onset of headache, visual symptoms, altered mental status, hormonal dysfunction

These lesions may also compromise the residual anterior pituitary sufficiently to produce hypopituitarism.

Question 35

Hypopituitarism

Answer 35

Hypofunction of the anterior pituitary may occur with loss or absence of 75% or more of the anterior pituitary functional cells.
Usually only one or few hormones deficient

Occasionally total failure (panhypopituitarism)

Question 36

Cause of hypopituitarism

Answer 36

Congenital (very rare)
More likely result from a range of acquired abnormalities.
Less frequently disorders that interfere with the delivery of hypothalamic releasing factors, e.g. hypothalamic tumors, may also cause hypofunction of the anterior pituitary.

Most cases of hypofunction are caused by:

Over half of all cases are caused by pituitary tumours
Non-functioning pituitary adenomas

Loss of over 75% of anterior pituitary functional cells

Ischemic necrosis (e.g. postpartum necrosis of the anterior pituitary (Sheehan syndrome), elevated intracranial pressure, traumatic injury, sickle cell anemia, shock)
Ablation by surgery or radiation
Inflammatory lesions (sarcoidosis, TB)
Trauma
Metastatic neoplasms

Question 37

Manifestations of hypopituitarism

Answer 37

Clinical manifestations will depend on the specific hormone lacking

Growth failure in children who lack GH (pituitary dwarfism)
Amenorrhea and infertility due to GnRH deficiency
Hypothyroidism (decreased TSH) or ACTH deficiencies
Adrenal insufficiency - ACTH
Amenorrhea - FSH, LH

Question 38

Abnormalities of hypopituitarism

Answer 38

Abnormalities of the primary level are far more common than those at the pituitary or hypothalamic level.

Question 39

Posterior pituitary hyper/hypofunction

Answer 39

Too much ADH → syndrome of inappropriate ADH or SIADH (caused by lung cancer)

Retains too much water

Not enough ADH → diabetes insipidus

Impaired water reabsorption (inappropriate dilute urine)

Polyuria and polydipsia

Question 40

Thyroid gland

Answer 40

The thyroid gland sits anterior to the trachea just below the larynx.
It consists of two lobes connected by an isthmus.
It produces 3 hormones:

T4 and T3 (from thyroglobulin by thyroid follicular cells)
Under stimulation from TSH

Calcitonin (produced by C cells).
Involved in calcium homeostasis

Question 41

Hormonal pathway of the thyroid gland

Answer 41

In response to thyroid hormone releasing hormone (TRH) released by the hypothalamus, thyroid stimulating hormone (TSH) is released from the anterior pituitary.
This stimulates thyroid follicular cells to produce T4 and T3 from the stored precursor protein thyroglobulin.

T3 and T4 enter circulation and are mostly bound to transport proteins such that the concentration of free (unbound) T3 and T4 is tightly regulated
Free T4 (prohormone) is largely converted to T3 (active hormone) via deiodinases
Thyroid hormone-receptor complex binds thyroid hormone response elements (TREs) in target genes
Serve to increase basal metabolic rate (promoting lipid and carb catabolism, promoting protein synthesis)

Secreted T3 and T4 inhibit release of TRH and TSH from the hypothalamus and pituitary, respectively.

Question 42

Hyperthyroidism

Answer 42

Excess thyroid hormone (T4 and T3) causes a hypermetabolic state known as thyrotoxicosis, resulting in number of symptoms

Constitutional symptoms: Heat intolerance, sweating, weight loss despite increased appetite
GI tract hypermotility and diarrhea (malabsorption)
Cardiac effects, including palpitations, increased HR (tachycardia)
Neuromuscular effects - tremor, nervousness, proximal muscle weakness

Ocular effects

Upper lid retraction (wide eyed stare)
Lid lag (secondary to stimulation of sympathetic nervous system of ocular muscles)

Question 43

Primary and secondary causes of hyperthyroidism

Answer 43

Primary causes:

Graves disease – an autoimmune condition resulting in thyrotoxicosis, ophthalmopathy, and infiltrative dermopathy
Hyperfunctioning “toxic” multinodular goitre
Hyperfunctioning “toxic” thyroid adenoma
Iodine excess

Secondary causes:

Pituitary adenoma (TSH secreting)

Question 44

Lab diagnosis of hyperthyroidism

Answer 44

Laboratory diagnosis of hyperthyroidism will show decreased TSH (majority of cases – notable exception is TSH secreting pituitary adenoma)
Increased free T4 and T3 levels
Radioactive iodine scans may be useful in determining etiology

Question 45

Grave’s diseases

Answer 45

Triad of manifestations

Thyrotoxicosis
Ophthalmopathy

Extraocular muscle and soft tissues expanded by lymphocytes/inflammatory cells, ECM components, fatty infiltration)
Gives eyes a bulging appearance

Infiltrative dermopathy (minority of patients)

“Pretibial edema”
Thickening of dermis by ECM components and lymphocytes

Autoimmune disease causes hyperfunction of the thyroid gland secondary to self-antibodies that bind and stimulate the TSH receptor (type II hypersensitivity disorder)

Question 46

Goitre

Answer 46

Enlargement of the thyroid gland

Diffuse or multinodular
Majority do not result in thyrotoxicosis (not releasing excess thyroid hormones)

Endemic vs. sporadic

Endemic goitre secondary to dietary iodine deficiency

Increased TSH causes hyperplasia and hypertrophy of the follicular cells (try to make more T3 and T4)

Sporadic goitre - most causes are idiopathic

May result in mass effects:
Airway obstruction
Obstruction of blood vessels (superior vena cava syndrome)

Occasionally may develop a hyperfunctioning nodule resulting in hyperthyroidism
Low incidence of developing malignancy (<5%)

Question 47

Hypothyroidism

Answer 47

Decreased circulating T4 and T3 hormones due to structural or functional abnormality interfering with their production.

Clinical manifestations include
Constitutional symptoms: sensitivity to cold, fatigue, weight gain
Decreased motility of GI tract: Constipation
Muscle weakness
Depression
Decreased heart rate (bradycardia).

Complications
Congenital hypothyroidism may result in “cretinism”, abnormalities in the skeletal and CNS resulting in mental retardation, short stature etc.
Longstanding, undiagnosed hypothyroidism may rarely result in “myxedema”, a potentially life-threatening complication.

Question 48

Causes of hypothyroidism:

Answer 48

Primary

Dietary deficiency of iodine (most common cause worldwide but not in developed countries
Autoimmune disease, including Hashimoto thyroiditis
Iatrogenic causes

Postablative, radiation therapy, radioactive iodine therapy
Drug effect
Developmental anomalies (rare)

Secondary

Pituitary failure (failure of TSH production)

Question 49

Diagnosis of hypothyroidism

Answer 49

Laboratory diagnosis of hypothyroidism will show increased TSH
Decreased free T4 and T3 levels (serum)

Question 50

Hashimoto thyroiditis

Answer 50

Autoimmune destruction of thyroid characterized by lymphocytic infiltrate with abundant germinal centers

Thyroid follicular cells undergo metaplastic change to “Hurthle” cells (appear large and eosinophilic)
Variable amount of associated fibrosis

Secondary lack of self-tolerance and likely involves

Antithyroid antibodies with resulting antibody-dependent cell cytotoxicity
CD8+ T cell mediated destruction of thyroid follicular cells
Excessive cytokine-mediated inflammation

Question 51

Thyroid adenomas

Answer 51

Typically round and solitary
Usually non-functional (not releasing hormone)
Occasionally will produce thyroid hormone resulting in hyperthyroidism.

Question 52

Thyroid carcinomas: Papillary carcinoma

Answer 52

Most common thyroid malignancy

85%
Non functional, present as painless mass
Indolent tumour with good prognosis
Metastasize to regional lymph nodes
Most common thyroid tumour associated with previous radiation (Chernobyl)

Question 53

Thyroid carcinoma: Follicular carcinoma

Answer 53

Less common (5-15%)
Usually non functional
Moderate prognosis
Spread by hematogenous dissemination, therefore regional lymph node metastasis uncommon

Question 54

Thyroid carcinoma: anaplastic carcinoma

Answer 54

Rare (<5%)
Highly aggressive, approaching 100% mortality (usually within 1 year)
Undifferentiated appearance (wild looking, a lot of necrosis, irregular shaped)
Associated with well-differentiated thyroid carcinoma in up to half of cases (developed from another carcinoma)

Question 55

Thyroid carcinoma: medullary carcinoma

Answer 55

Arise from calcitonin-producing neuroendocrine cells (non epithelial of the thyroid, C cells)

Uniform appearance
Calcitonin stains brown

Tumour cells are polygonal to spindle-shaped

Usually produce calcitonin

Up to ⅓ of cases are associated with familial syndrome (multiple endocrine neoplasia (MEN types 2A, 2B and familial medullary thyroid carcinoma) associated with germline mutations in the RET gene

Question 56

Adrenal glands

Answer 56

Sit at the upper pole of each kidney
2 endocrine glands: cortex and medulla

Question 57

Adrenal cortex

Answer 57

Produces three groups of steroid hormones

Glucocorticoids - sugar-protein metabolism
Mineralocorticoids - water-electrolyte balance
Sex steroids - sexual function

3 layers/zones

Zona glomerulosa - outermost

Aldosterone secretion (mineralocorticoid)
Stimulated by angiotensin and K+
Inhibited by atrial natriuretic peptide and somatostatin to regulate blood pressure

Zona fasciculata - 75% of cortex

Secrete glucocorticoids (corticosterone and cortisol)
Under ACTH control

Zona reticularis - innermost layer

Secrete sex steroids (mostly androgens and small amounts of estrogens)
Under ACTH control

Question 58

Adrenal medulla

Answer 58

Produces epinephrine, norepinephrine

Question 59

Steroid hormone production in the adrenal cortex

Answer 59

Zona reticularis - androgens produced
Zona fasciculata - glucocorticoids
Zona glomerulosa - mineralocorticoids
Key enzymatic step - 21 hydroxylase

Convert androgens to produce cortisol molecules (glucocorticoids)
Zona fasciculata

Question 60

Cushing’s syndrome

Answer 60

Caused by adrenocrotical excess (excess glucocorticoids)

Wide-spread effects

Abnormalities of fat distribution - moon facies, Buffalo hump, centripetal obesity.
Abnormalities of protein - basically protein loss, for example muscle loss or osteoporosis.
Abnormalities in metabolism - increased glucose, decreased potassium, increased blood pressure.

Question 61

Causes of Cushing’s disease

Answer 61

The most common cause of this syndrome is actually the long-term administration of corticosteroids that are given medically for a variety of conditions (e.g. for treatment of inflammatory or immune disorders).

Pituitary adenoma - corticotroph cell adenoma → secretes excess ACTH → high ACTH and high cortisol
Excess glucocorticoids can arise in other situations → cushing’s syndrome

Endogenous causes include:

Most commonly, pituitary adenoma (80% of endogenous causes) which is known as Cushing’s Disease or corticotropin-dependent adrenal hyperfunction
Adrenocortical neoplasms (10%)
Production of ACTH by non-endocrine tumours (10%) known as the ectopic (paraneoplastic) ACTH syndrome.

Question 62

ACTH production in Cushing’s disease

Answer 62

As ACTH is produced, other hormones are also produced from the prohormone (e.g. MSH)
Can lead to hyperpigmentation of skin

Question 63

Cushing’s disease at the pituitary level

Answer 63

The pituitary produces ACTH (corticotropin) and the adenomas that cause Cushing’s disease do so by producing too much ACTH.

ACTH in the blood in this condition will be high.

Also a CT or MRI scan can now detect even small abnormalities in the pituitary.

Pathologically the adenomas producing Cushing’s disease are benign neoplastic growths of cells producing ACTH.

The small neoplasms would probably be clinically totally unnoticed except for their hormonal production.
The adrenals respond to the excess by showing symmetrical bilateral hyperplasia, distinct from the neoplasms of the adrenal, outlined below.
The therapy for this condition is surgical removal of the pituitary adenoma and is highly effective.

Question 64

Cushing’s disease at the adrenal cortex level

Answer 64

The adrenal cortical neoplasms responsible for Cushing’s syndrome are of two types: adenomas (benign) or carcinomas.

In both cases ACTH will be low as the pituitary is suppressed.
Low ACTH and high cortisol

These lesions can also be detected on CT scan.
Surgery is the therapy of choice.

Inappropriate hormone production
In syndromes of ectopic ACTH production the clinical picture is quite different.
These patients have cancer of other organs, most commonly cancer of the lung.
Thus, they often appear obviously quite ill or wasted.
The syndrome is often severe and rapid in onset and patients do not have time to develop the fat and protein disturbances characteristic of the other types of Cushing’s syndrome.
The ectopic ACTH syndrome is dominated by metabolic features.
ACTH will be very high.
The adrenals pathologically will again show symmetrical hyperplasia, but to a far greater degree than that seen in the pituitary disease.

Question 65

Excess Mineralocorticoids

Answer 65

Excess aldosterone secretion

Aldosterone enhances sodium retention in renal tubules and potassium excretion
Water and increased volume
This situation is much simpler than with excess glucocorticoids.

Manifestation:
Hypertension with a low serum potassium.
More common in women than men (3:1)
Ages 30-50 years
Two types of pathology account for excess mineralocorticoids:
Benign adenoma (Conn syndrome or Conn’s Tumour)
75%
Diffuse hyperplasia.

Treatment
Medicine to block the effects of mineralocorticoids (aldosterone)
Surgical removal of the adrenal(s).

Question 66

Excess sex steroids

Answer 66

Usually due to
Neoplasms (most often adrenal adenocarcinoma)
Congenital adrenal hyperplasia
Clinical manifestations (excess androgens)
Precocious puberty in children
Virilization/masculinization in women
Feminization in men.
Oligospermia in older males (decreased sperm production)
In adults it is almost always caused by adrenocortical carcinoma.

Question 67

Congenital adrenal hyperplasia (CAH)

Answer 67

All the examples we have discussed so far have been acquired.
Cause: results from a number of autosomal recessive enzymatic defects in the biosynthesis of cortisol from cholesterol
Deficiency of 21 hydroxylase (90% of cases)
Converts 17-OH-progesterone to 11-deoxycortisol
Impaired cortisol synthesis
Precursors converted to androgens
Enlarged adrenal glands due to increased ACTH (no negative feedback)
Virilizing CAH
Female infants exhibit pseudohermaphroditism
Depending on enzymatic defect may also see salt-wasting CAH if aldosterone synthesis is also impaired
Hyponatremia, hyperkalemia, dehydration, hypotension, increased renin secretion → may be fatal
In this condition one of the enzymes used to produce glucocorticoids, and sometimes mineralocorticoids, is abnormal.
The precursors are thus diverted to production of sex steroids, resulting in virilization of newborns, including pseudo-hermaphroditism of baby girls.
Sometimes infants will also suffer from serious imbalances of water and electrolytes.
Treatment
Exogenous replacement of cortisol
Mix of glucocorticoids and mineralocorticoids to reduce ACTH and provide missing hormones

Question 68

Hypoadrenalism

Answer 68

The adrenal, like most endocrine organs, has a large functional reserve, i.e. most of it can be destroyed before clinically important consequences are noticed.
The most common cause of chronic hypoadrenalism in developed countries is an autoimmune disease called Addison Disease.

Adrenal here becomes small and fibrotic and microscopically shows a lymphocytic infiltrate.

Causes:
Autoimmune disease (autoimmune adrenalitis) is most common
Progressive destruction of adrenal gland
Infection
Tuberculosis
Opportunistic infections (HIV associated)
Metastatic disease

Clinical manifestations
The lack of adrenocortical hormones will produce apathy, decreased blood pressure, decreased blood glucose, increased potassium, and decreased sodium.
Decreased mineralocorticoids
These patients often become hyperpigmented.
Decreased corticol → increased ACTH production and increased MSH
Reaction of the pituitary to the low glucocorticoids is to produce excess ACTH and a related hormone, melanocyte stimulating hormone (MSH)

Treatment
Exogenous hormonal replacement
Corticosteroids, mineralocorticoids
Acute conditions is a consideration due to sudden withdrawal of steroids and stress

Question 69

Acute adrenocortical insufficiency

Answer 69

Much more dramatic than chronic hypoadrenalism

Causes:
Massive adrenal hemorrhage (Waterhouse-Friderichsen syndrome)
Often associated with meningococcal bacteria (sepsis)
Sudden withdrawal of long-term exogenous corticosteroid therapy (should be tapered)
Stress in patients with chronic adrenal insufficiency
Anticoagulated patients
Disseminated intravascular coagulation (DIC)
Sepsis
Clinical manifestations
The consequences of cardiovascular collapse and marked electrolyte disturbances can be fatal.
Emergency steroid therapy is necessary to treat this condition.

Question 70

Endocrine pancreas

Answer 70

Pancreas has a neck, head, and body
There are two main compartments of the pancreas, the endocrine pancreas and exocrine pancreas.
The endocrine pancreas is composed of 4 main cell types that are organized into islets of Langerhans.

Each of these cell types produces a hormone:
Alpha cells produce glucagon
Raises blood glucose levels via action on hepatocytes
Beta cells produce insulin
Regulates glucose utilization in cells thereby reducing blood glucose levels
Delta cells produce somatostatin
Suppresses insulin and glucagon secretion
PP cells produce pancreatic polypeptide
Gastrointestinal effects - secretion of gastric/intestinal enzymes, inhibition of intestinal motility
Acinar cells: acini formed
Consist of acinar cells surrounding a central duct
Contains granules secreted into the lumen → delivered
Ductal cell

Question 71

Diabetes mellitus

Answer 71

A group of metabolic disorders, all characterized by hyperglycemia.
Has a huge impact on the North American Health Care system, affecting approximately 10% of the U.S. population (400 million worldwide)
7th leading cause of death in the USA
Consumes 1 of 12 global health care dollars spent
Lack of inadequate glucose uptake into tissues → excessive glucose in circulation → cellular damage
Chronic disease is both initiated and propagated by inflammatory cells and cytokines which are elevated and sustained at a low-grade throughout the disease
Endothelial cells are the principal cell type affected by hyperglycemia
Due to protective barrier function

Question 72

Basic classification of diabetes (majority of cases)

Answer 72

Type I diabetes – Beta (β) cell destruction via an autoimmune process resulting in absolute insulin deficiency
Type II diabetes – relative insulin deficiency secondary to peripheral insulin resistance and inadequate insulin secretion response by the pancreas.
Other (less common) causes
Genetic abnormalities of beta cells or insulin function
Exocrine pancreas pathology (tumours, pancreatitis, surgeryk, CF)
Endocrinopathies (excess hormones - GH, Cushing, hyperthyroidism)
Infection
Drugs
Gestational diabetes

Question 73

Pathogenesis of diabetes

Answer 73

Type I DM: immune-mediated destruction of β cells (failure of self-tolerance in β cell-specific T Cells).

Can present at any age, but mostly in childhood. Involves both genetic susceptibility (eg. MHC II genes, polymorphisms in insulin gene), and environmental factors (possibly viral antigens mimicking β cell antigens, however no conclusive evidence for this).
Type II DM: Insulin resistance and beta cell dysfunction.

Insulin resistance is the failure of target tissues (mainly liver, skeletal muscle and adipose) to adequately respond to insulin.
It is associated with obesity, which has led to the term metabolic syndrome (obesity, insulin resistance, glucose intolerance, and cardiovascular risk factors).
β cell dysfunction occurs when these cells can no longer maintain increased output of insulin to compensate for peripheral insulin resistance and maintain normal blood glucose levels, leading to a state of relative insulin resistance.

Question 74

Diagnosis of diabetes mellitus

Answer 74

Fasting plasma glucose ≥7.0 mmol/L (normal range 3.3 – 5.8 mmol/L)
HbA1C ≥6.5% (adults; not for diagnosis of type I DM) (normal range 4 – 6%)
2 hour plasma glucose of ≥11.1 mmol/L following oral glucose tolerance test
Random plasma glucose of ≥11.1 mmol/L

Question 75

Complications of diabetes mellitus

Answer 75

Acute metabolic complications (mostly seen in Type I DM)
Polyuria, polydipsia, and polyphagia:
Hyperglycemia exceeds renal thresholds for glucose resorption resulting in glycosuria (too much glucose in urine), which in turn causes osmotic diuresis and polyuria, causing dehydration and electrolyte loss.
Dehydration triggers osmoreceptors in the brain resulting in intense thirst – polydipsia.
Proteins and fats are catabolized as a potential energy source, resulting in increased appetite – polyphagia.

Ketoacidosis:
In addition to polyuria and dehydration, insulin deficiency combined with stressors (infection, unusual physical activity, heart attack, large deviations from normal diet etc.) may lead to production of ketones which are produced in the liver from the increased free fatty acids produced from excessive lipolysis.
Ketones can be used as an emergency energy source in times of starvation
When combined with dehydration may not be adequately excreted in the urine, leading to decreased blood pH – ketoacidosis.

Chronic complications (Type I and type II DM)

Macrovascular:
Accelerated atherosclerosis, leading to coronary atherosclerosis and myocardial infarction (most common cause of death in diabetics)
Peripheral vascular disease, leading to ischemic necrosis (gangrene) of lower extremities (100 fold more common in diabetics)
Hyaline atherosclerosis – associated with hypertension, but more common in diabetics than general population

Microvascular (microangiopathy)
Diabetic nephropathy (renal failure, 2nd most common cause of death in diabetics)
Diabetic retinopathy (diabetes is a common cause of acquired blindness)
Diabetic neuropathy – most commonly affects nerves of distal extremities (“stocking and glove” distribution of polyneuropathy).
Can also cause autonomic neuropathy, leading to bowel/bladder/erectile dysfunction, etc.