Endocrine Pathophysiology

Question 1

thyroid

What do follicular cells do and what ingredients do they receive from the blood?

Answer 1

Follicular cells
Synthesize, store and secrete thyroid hormone
Three ingredients derived from blood/serum:
Tyrosine (and other amino acids)
Iodide
Carbohydrates

Question 2

How is thyroidhormone synthesis established?

Answer 2

Hormone synthesis
1) Thyroglobulin is glycoprotein made up from iodine and tyrosine
2) Iodine is oxidized from iodide by thyroperoxidase
3) Final assembly of thyroid hormone occurs extracellular.

Question 3

What hormones are secreted fromthe thyroid and how?

Answer 3

Hormone secretion
1) Endocytosis of thyroglobulin (including elongation of microvilli) is stimulated by Thyroid stimulating hormone (TSH)
2) Colloid droplets fuse with lysosomes to release thyroxine (T4) and triidothyronine (T3) the active forms of thyroid hormone.

Question 4

What do T3 and T4 hormones do?

Answer 4

Effects of T3 > T4 (but both similar):
Free hormone enters the cell
Ultimately bind to high affinity nuclear receptors
Bind hormone-activated transcription factors
Bind mitochondrial receptors on the inner mitochondrial membrane > increased oxidative phosphorylation (increased O2 consumption)
Increased metabolism and increased protein synthesis
Effects on the cardiovascular system:
1) increased heart rate (HR)
2) increased contractility
3) increased cardiac output (CO)
4) vasodilation
In the nervous system thyroid hormones act on B-adrenergic receptors, leading toenhancement of the sympathetic nervous system.

Question 5

Which cells inthe thyroid secrete calcitonin?

Answer 5

C Cells (AKA: parafollicular or ultimobranchial cells)
Located between follicular cells or between follicles
Secrete calcitonin in response to hypercalcemia.

Question 6

Histology of thyroid lesions associated with hypothyroidism: lymphoplasmacytic thyroiditis

Answer 6

Thyroid gland infiltrated with lymphocytes, plasma cells and macrophages = lymphoplasmacytic thyroiditis

• Multifocal to diffuse infiltration of inflammatory cells
• C cells more prominent (nests)
• Lack of colloid, inflammatory cells in colloid, colloid vacuolated
• Overall loss of follicles

Question 7

histology lesions for idiopathic follicular collapse

Answer 7

Idiopathic follicular collapse
- Loss of follicular epithelium
- Disruption of follicles
- Lack of colloid/vacuolated
- Replacement with adipose tissue

Question 8

histological lesion for: thyroid hypoplasia

Answer 8

follicular cells are low cuboidal
Full of colloid, distended
No evidence of active endocytosis

This is what thyroid would look like if either no stimulation with TSH (non-functional pituitary adenoma) or high circulating thyroid hormone (exogenous thyroxine administration)

Question 9

in hypothyroid related lesions: Besides low T4/T3, what is one other common clinical pathologic finding?

Answer 9

Hyperlipidemia/hypercholesterolemia:
Hepatomegally
Glomerular and corneal lipidosis
Atherosclerosis (important but not common)

Pathogenesisof artherosclerosis: Decreased thyroid hormone à decreased lipid breakdown à hypercholersterolemia à endothelial damage à increased permeability and mobilization of macrophages à atherosclerosis

Question 10

Presentation and pathology of the skin during hypothyroidism?

Answer 10

Skin:
Symmetric alopecia
Hyperkeratosis/follicular hyperkeratosis

Pathogenesis: Hypothyroidism > no stimulation of follicular epithelial cells > increased number of follicles in telogen (resting state) >progressive alopecia

Myxedema

Accumulation of glycoaminoglycans and hyaluronic acid -> bind water
May be “normal” for what breed:
Sharpei

Question 11

what is the pathogenesis and causes of goiter?

Answer 11

Pathogenesis: Inadequate thyroxine synthesis > Hypothalamus senses low T3/T4 > pituitary secretes more TSH > thyroid hyperplasia

Causes:
Iodine deficiency
Goitrogenic compounds:
Thiouracil
Sulfonamides
Thyocyanates
Brassicaceae family of pants
Cabbage, broccoli, turnips
Excess iodide (too much iodine disrupts colloid endocytosis)
Congenital

Answer 12

Functional hyperplasia (often multi-nodular)
Note band of thyroid tissue between two hyperplastic nodules (n): Low cuboidal epithelium and distended with colloid = non-functional due to high circulating levels of T3/T4

Question 13

hyperthyroidism is Less common in dogs than cats – why?

Answer 13

Dogs have very efficient enterohepatic clearance of thyroid hormone

Question 14

what are the clinical signs of hyperthyroidism? how does it affect the cardivascular system?

Answer 14

Clinical signs are manifestations of increased metabolic rate:
Weight loss despite voracious appetite
PU/PD secondary to increased GFR
Excitability, nervousness, poor grooming
Weakness, hyperthermia
Common clinical pathology changes: High T3/T4, elevated ALT, AST, and ALP, hypophosphatemia and low iCa++ (hyperparathyroidism), azotemia? (may mask underlying renal disease because increased GFR)

Cardiovascular (most clinically significant manifestations – need immediate treatment!!!)
Tachycardia
Hypertension
Retinal detachment
Hypertrophic cardiomyopathy  saddle thrombus
HCM: Concentric hypertrophy

Question 15

what is the pathogenesis of hyperthyroid to a saddle thrombus?

Answer 15

Hyperthyroid  cardiomyocyte stim/peripheral vasodilation  HCM  LA thrombosis  thromboemolism  saddle thrombus

Question 16

what types of thyroid neoplasia is common in which species?

Answer 16

Functional or non-functional
Follicular vs. C Cell (parafollicular)
Adenoma vs. Carcinoma
Cats: follicular adenoma – functional
Dogs: follicular carcinoma
Bulls: C Cell adenoma or carcinoma - functional
Horses: follicular adenoma > C cell adenoma

Question 17

What are the common thyroid neoplasia and how do they present in our common species and what types do they have?

Answer 17

Clinical presentation and outcome will depend on:
Adenoma vs. carcinoma
Functional vs. non-functional
Cell of origin – Follicular vs. C Cell (AKA medullary, parafollicular, ultimobranchial)
Stains for thyroglobulin or calcitonin can be used to differentiate if necessary
Note: Can arise in accessory (or ectopic) thyroid tissue as well!!

Follicular Adenoma
Most common in cats (which species)
Often encapsulated and freely movable
Compresses adjacent tissue
Well – differentiated (can clearly identify follicles)
Bilateral adenoma > carcinoma

Follicular Carcinoma
Most common in dogs
Invades adjacent tissue – fixed (NOT movable)
Can be follicular, but less organized and less differentiated
Vascular invasion, esp. thyroid vein
Metastasis to lungs and lymph nodes (lungs may be first)

C-cell or medullary adenoma/carcinoma
Two species in which these are most common?
Typically non-functional adenomas in older horses
Functional adenoma or carcinomas in bulls
May occur with other endocrine tumors - similar to MEN syndrome in humans but:
Don’t always affect same set of encdocrine tumors
No underlying mutations have been identified.

Sheets/nests of cells separated by stroma +/- amyloid +/- follicles/colloid

Carcinomas metastasize to cervical lymph nodes

Question 18

what is the goal of PTH and its target organs?

Answer 18

Effect of PTH on target organs:
Goal of PTH is to increase levels of calcium in the blood.
More calcium in extracellular fluids (ECF) = more calcium in blood.
Bone:
Increases activity of osteoclasts (and osteocytes) to allow mobilization of calcium out of bone into ECF.

Kidney:
Stimulates reabsorption of calcium in the distal convoluted tubule and inhibits absorption of phosphorus in the proximal tubule.
Overall effect is increased calcium in the ECF and decreased loss of calcium in the urine.
Overall effect on phosphorus is decrease phosphorus in the ECF and increased excretion of phosphorus in the urine.
Increased vitamin D synthesis (inhibited by phosphorus).

Intestine:
Stimulates absorption of calcium and phosphorus in the intestine secondary to increased vitamin D.
Three major hormones involved in regulation of calcium metabolism and skeletal remodeling: PTH, calcitonin, vitamin D.

Question 19

what are the three main mechanisms of hyperparathyroidism?

Answer 19

primary is unilateral enlarged neoplasia. Funcitonal adenoma is more common.

secondary is bilateral enlarged hyperplasia. Two categories:
Nutritional imbalance:
Three cuases: Diets high in phosphorus, Diets low in calcium, Low dietary or environmental vitamin D
Renal disease:
Pathogenesis: Chronic renal failure > decreased GFR > increased Phosphorus > Decreased iCa++ > hyperparathyroidism
In both cases hypocalcemia drives the hyperparathyroidism. Parathyroids are typically bilaterally enlarged.

PHTrP and HHM is bilateral atrophy.
three cancers commonly associated with HHM: lymphoma, multiple myeloma, anal sac adenocarcinoma

Question 20

what two species that may have higher blood levels of calcium compared to most domestic animals

Answer 20

horses and rabbits

Question 21

What are the three main cell types in the pancreas islets of langerhans and what do they secrete?

Answer 21

alpha: glucagon
beta: insulin
delta: somatostatin

Question 22

What are the three target organs/cells of insulin and does it have a primarl;y catabolic or anabolic effect?

Answer 22

liver, fat, muscle

anabolic

Carbohydrate metabolism:
- Inhibits liver from making new sugar (glyoconeogenesis), or breaking down glycogen stores (glycogenolysis)
-Inhibits mobilization/utilization of glucose stored in muscle

Lipid metabolism:
- Inhibits mobilization of fatty acids/promotes synthesis of fatty acids
- Inhibits breakdown of lipids (lipolysis)/promotes synthesis of lipids (lipogenesis)

Question 23

how does insulin resistance occur?

Answer 23

Insulin Resistance (IR):
Normal adipocytes associated with resident macrophages (M1) – FFA released at low levels as necessary
Vs.
In obesity  large numbers and size of adipocytes leads to increased release of FFA and “adipokines” = inflammatory mediators released by adipocytes  infiltration by inflammatory macrophages (M2)  release of additional inflammatory mediators  inflammation inhibits normal insulin triggered signaling pathways  insulin resistance!!!!

Question 24

Whatis a unique sequela of DM in cats and dogs

diabetes mellitus

Answer 24

Unique sequela in the cat: peripheral demyelinating neuropathy
Unique sequela in the dog: cataracts
Pathogenesis: Glucose enters the lens  converted to sorbitol by aldose reductase  sorbitol accumulation  lens degeneration.
*Why doesn’t this typically happen in cats? lower levels of aldose reductase in the lens

Question 25

Why is DM so hard to control in some animals?

Answer 25

Why so hard to control in some animals? In part due to insulin antagonists including **glucagon, growth hormone, catecholamines, glucocorticoids, etc. **(many of these cases present as a result of concurrent disease).
All of these, especially glucagon, may lead to increased oxidation of fatty acids  produces keytones (ketogenesis)  DKA
Metabolic derrangements and/leading to dehydration/hypovolemia  hypercoaguability  infarcts  systemic dysfunction/DIC = CRITICAL  your DM patients may present this way before you diagnose DM!!!