Pathoma-Lecture-Notes

- Causes - damage (tumor, trauma, infection or inflammation) to hypothalamus or pituitary
- Diagnosis - urine osmolality doesn't increase in response to water deprivation
- Treatment - Desmopressin (ADH analog)
11. What are clinical presentation and causes of nephrogenic diabetic insipidus?
- Presentation - same as central DI but no response to desmopressin
- Causes - mutation or drugs (demeclocycline - old antibiotic, not used often now; and lithium)
12. What are clinical presentation and causes of syndrome of inappropriate ADH (SIADH)?
- Presentation -

○ Hyponatremia and low serum osmolality
○ Mental status change and seizure. - due to nerve swelling
- Causes - ectopic production (ex - small cell carcinoma of lung)
○ CNS trauma
○ Pulmonary infection
○ Drugs (cyclophosphamide)
- Treatment - free water restriction, demeclocycline

Endocrine Page 1.3

15.3-15.7 Thyroid

1. Differentiate T3 and T4

T4 (thyroxine) T3 (triiodothyronine)

Both are made from tyrosine 10 times more potent than T4

Most of it made from T4

Thyroid secretes T4>>T3

T1/2 = 7 days T1/2 = 7 days

T4--> T3 conversion reduced in severe illness

2. How are thyroid hormones transported in blood?
- Tyrosine binding protein (carries 70%)
- Albumin (carries 20%)
- Transthyretin (pre-albumin) (carries 10%)
- Free T4 is 0.04% and free T3 is 0.03%

3. How are T3 and T4 made in thyroid gland? What is the key enzyme?
- Key enzyme is thyroid peroxidase
- Thyroglobulin are long chain of tyrosine that's stored as colloid in thyroid gland. T3/T4 are made

from it.
- Steps

○ Iodine is oxidized to oxidized iodine by thyroid peroxidase (oxidation step)
○ Oxidized iodine reacts with tyrosine to make monoiodotyrosine
○ Oxidized iodine reacts with monoiodotyrosine to make diiodotyrosine
○ The last two steps are called organification
○ Monoiodotyrosine + diiodotyrosine = triiodothyronine
○ Diiodotyrosine + diiodotyrosine = thyroxine
○ The last two steps are called coupling

4. What are functions of thyroid hormones?
a. Increase or decrease gene transcription by binding to nuclear receptor
b. Imp in development (Cretinism is mental retardation and dwarfism caused due to
impairment of brain and skeletal development due to hypothyroidism)
c. Increase BMR, O2 consumption and free radical formation
d. Exacerbate diabetes mellitus (increase glycogenolysis and increase hepatic gluconeogeneis)
(hyperthyroid = DM)
e. Increase LDL receptors (hyperthyroidism = low serum LDL)
f. Increase ionotropy (contractility), chronotropy (HR),
g. Increase sensitivity to catecholamine for B1 receptors(hyperthyroidism = hyperactive SANS)
h. Pulm - maintains hypoxic and hypocapnic drive (hypothyroid = hypoventilation and
respiratory arrest)
i. GI - increase gastric motility (hypothyroid= constipation, hyperthyroid = diarrhea)
j. Skeletal - increase bone reasborption and decrease bone formation (hyperthyroid =
osteopenia)
k. Neuromuscular - (hyperthyroid = increased reflex, anxiety, hyperactivity; hypothyroid =
decreased reflexes, fatigue and sluggish)

5. What causes thyroglossal duct cyst? (HY)
- Thyglossal duct is a path for descent of thyroid from tongue to its location in neck. The cyst dies

Endocrine Page 2.1

- Thyglossal duct is a path for descent of thyroid from tongue to its location in neck. The cyst dies
out normally; if it persists, it may cause cystic dilation and seen as anterior neck mass.

6. What causes lingual thyroid?
- If thyroid tissue persists at base of tongue, it's present as a mass.

Hyperthyroidism (thyrotoxicosis)
7. What are presentation of hyperthyroidism?
a. Increased basal metabolic rate (due to increased synthesis of Na/K pump) (HY) -
i. wt loss despite increase hunger
ii. Tremor, anxiety, insomnia, and heightened emotions
iii. Heat intolerence and sweating
b. Increased SANS (due to increased expression and activity of B1 s)
i. Cardiac - tachycardia, arrhythmia (esp in elderley)
c. Hyperglycemia (increased gluconeogenesis and glycogenolysis) (HY)
d. Hypocholesteremia and low serum LDL (increased LDL receptors) (HY)
e. Diarrhea and malabsorption (increased GI motility)
f. Osteopenia and hyercalcemia (increased bone reabsorption)
g. Decreased muscle mass and weakness
h. Oligomenorrhea

8. What is epidemiology of Grave's disease? What is it?
- Most common cause of hyperthyroidism
- Classically occurs in women of childbearing age (this group has high incidence of autoimmune

disease)
- Grave's is autoantibody IgG generation that stimulates TSH receptor leading to hyperthyroidism

(type II hypersensitivity)

9. What are clinical presentation of grave's disease?
- Diffuse goiter - TSH hormone is a trophic hormone that leads to hyperplasia and hypertrophy
- Tibial myxedema and exopthalmus

10. What causes exopthalmos and pretibial myxedema (characterstic finding) in grave's?
○ Fibroblast behind eye and in tibia has TSH receptors. Excitation leads to glycosaminoglycan
(chondroitin sulfate and hyaluronic acid) buildup, inflammation, fibrosis, and edema.
○ Myxedema feels like dough. And myx refers that edema is not caused by water.

11. What is histology of Grave's?
- Histology shows irregular follicle and scalloped colloid and chronic inflammation

Endocrine Page 2.2

Fig - Thyroid in grave's. Notice irregular follicles. Also, the white space between colloid and
thyroid tissue is called scalloped and is classic occurrence in Grave's.

12. What is treatment of Grave's?
- B-blockers
- Antithyroid durgs (methimazole, propylthiouracil, thyoamide) - concentrate in thyroid and block
thyroid peroxidase; also prevent T4 --> T3 conversion in peripheral tissue
- I-131 - thyroid takes it and gets destroyed (permanent hypothyroidism major complication)
- Total thyredctomy

12.5. What are lab findings in Grave's?
- Increased total and free T4
- Decreased serum TSH
- Hypocholesteremia (HY)
- Hyperglycemia (HY)

13. Differentiate thyroid storm vs myxedema coma Myxedema coma
Thyroid storm (hyperthyroid emergency) (hypothyroid emergency)
Presentation- mental
Presentation - fever (>400C), sweating, tachycardia/afib, delirium, status change from
nausea, vomiting confusion to coma
Hypoglycemia,
Cause - increased catecholamines action and massive T3/T4 excess. hypothermia,
Most common trigger - acute stress such as surgery, childbirth, MI. hypothermia,
hypoventilism
Treatment High incidents of death
- B-blockers, propylthiouracil, and steroids
- give Iodine salt (wolff-chaikoff block - increased iodine in Treatment- high dose of
blood leads to decreased iodine uptake by thyroid and levothyroxine
decreased production of thyroid hormones) Cause- infection, stroke, in
patients with
hypothyroidism

Endocrine Page 2.3

14. What causes multinodular goiter? Is it toxic?
- Multiple nodules and enlarged thyroid
- Caused due to relative iodine deficiency
- Usually nontoxic (rarely, some regions can be toxic, i.e., produce T3/T4)

Fig - multinodular goiter

Hypothyroidism
15. What is cretinism? What are it's findings?

- It's developmental delay caused due to hypothyroidism.
- Classic findings

○ Mental retardation and dwarfism due to poor brain and skeletal development
○ Enlarged tongue (due to myxedema)
○ Umbilical hernia

16. What are causes of cretinism?
- Maternal hypothyroidism during early pregnancy
- Thyroid agenesis (pt don't develop thyroid)
- Dyshormonogenic goiter (pt can't make thyroid hormones - ex - pt with mutation in thyroid
peroxidase gene)
- Iodine deficiency

17. What's classic findings in myxedema (hypothyroidism in old kids and adults)?
a. Myxedema - classically in tongue (large tongue) and larynx (gives deep voice) (HY) - due to
increased TSH
b. Decreased BMR and decreased SANS
i. Wt. gain despite normal activity
ii. Cold intolerane and decreased sweating
iii. Bradycardia
c. Hypoventilation and respiratory arrest - thyroid maintains respiratory drive
d. Slow mental activity
e. Muscle weakness
f. Hypoglycemia, hypercholesteremia
g. Oligomenorrhea (seen in both hyper and hypothyroidism)
h. Constipation

18. What are causes of hypothyroidism?
- Hashimoto's (most common cause)
- Iodine deficiency
- Drugs (lithium)

Endocrine Page 2.4

- Drugs (lithium)

Thyroiditis
19. What is presentation of hashimoto's thyroiditis? What chemical is is associated with? What are lab

results?
- It's an autoimmune attack to thyroid peroxidase and thyroglobulins
- Associated with HLA-DR5 (HY)
- Initially see increase T3/T4 (and low TSH) due to gland destruction. Later on, we see decreased

T3/T4 (and high TSH) due to gland destruction.
- Suspect other autoimmune disease - type 1 DM, pernicious anaemia, rheumatic disease.
- Lab results - anti TPO, anti-thyroglobulin, anti-microsomal antibodies, high TSH, low T3/T4

20. What is histologic appearance of Hashimoto's thyroditis? (HY)
- Chronic inflammation (see lymphocytes) with germinal cells.
- Presence of Hurthle cells (eosinophilic metaplasia of cells that line follicles).

Fig - Hashimoto's thyroiditis. CI is chronic inflammation. GC is germinal center. Little circles
on left are herthel cells.

21. What disease do pt. with Hashimoto's have increased risk of? How? What's presentation?
- B cell lymphoma.
- How - Germinal center makes post germinal center B cells. It makes marginal zone which results in
marginal zone lymphoma.
- Presentation is pt with long standing hypothyroidism that presents with enlarged thyroid.

22. What is SUBACUTE GRANULOMATOUS (DE QUERVAIN) THYROIDITIS? What's its presentation?
What's its prognosis?

- It's granulomatous thyroiditis that follows viral infection (subacute means it occurs after acute
process).

- Presentation - Hypothyroidism is transient, and pt has tender thyroid (if a young female has tender
thyroid, think subacute granulomatous thyroiditis).

- Prognosis - It's self-limited and don't progress to hypothyroidism.

23. What is Reidel Fibrosing thyroiditis? What is presentation?
- Chronic inflammation of thyroid with extensive fibrosis
- Presentation -
○ hard as wood thyroid that's non tender
○ Fibrosis may extend to local structures - ex - airway
Clinically mimics anaplastic carcinoma but pt are younger and usually female(in anaplastic,

Endocrine Page 2.5

○ Clinically mimics anaplastic carcinoma but pt are younger and usually female(in anaplastic,
pt are older)

Thyroid cancer
24. What are basics of thyroid cancer?

- Most nodules are distinct and solitary
- Most nodules are likely to be benign than malignant
25. What causes positive and negative in radioiodine uptake study?
- Positive is when thyroid takes radioiodine injected in blood - Graves, nodular goiter
- Negative - adenoma and carcinoma (do biopsy by FNA)
26. Describe follicular adenoma (adenomas are benign; adenocarcinoma are cancerous).
- Follicle proliferate in a benign way and are surrounded by a fibrous capsule
- Called follicular because tumor also makes thyroid follicle.
- Tumor mostly non-functional (don't secrete hormone)

Fig - follicular adenoma. Red line is the capsule that divides adenoma (bottom half) from
normal thyroid (top half)
27. What are 4 types of thyroid carcinomas (malignant stuff)?
a. Papillary carcinoma
b. Follicular carcinoma
c. Medullary carcinoma
d. Anaplastic carcinoma
28. What is epidemiology, risk factor, prognosis and histologic feature of papillary carcinoma?
- Most common thyroid carcinoma (80% of thyroid carcinoma)
- Major risk - exposure to ionizing radiation in childhood
- Prognosis - excellent even though often spreads to cervical nodes
- Histology -
- Papillae of cells seen (so called papillary carcinoma
- Diagnosis is made by nuclear features -

 Coffee bean nucleus (presence of nuclear groove)
 Orphan eye annie nucleus (nucleus has white stuff resembling white of eye)
 Psammomma bodies (concentric calcification of papillaes).

Endocrine Page 2.6

Fig - Papillary carcinoma. red circles indicate orphan eye annie nucleus. Turquoise circle
shows coffee bean nucleus.

Fig - Psammoma bodies in papillary carcinoma shown in black circle.
29. What is histologic feature of follicular carcinoma? Can you diagnose by FNA?

- Similar to follicular adenoma (has fibrous capsule) but cells invade through capsule (hallmark)
- FNA can't distinguish between follicular adenoma and follicular carcinoma because capsular

invasion can't be assessed by FNA.
- Even though most carcinomas spread via lymph nodes, follicular carcinoma spreads

hematogenously (by blood).

Endocrine Page 2.7

Fig - follicular carcinoma. Red line shows the capsule and the break in it.
30. What are 4 carcinomas that spread by blood instead of lymph? (HY)

- Renal cell carcinoma
- Follicular carcinoma of thyroid
- Hepatocellular carcinoma
- Corneal carcinoma
31. Describe medullary thyroid carcinoma (MTC). How is it diagnosis?
- Malignant proliferation of parafollicular C cells that produce calcitonin
- Diagnosis -

○ Malignant cells in amyloid stroma - indicates MTC. (Calcitonin deposits in tumor as amyloid
(cause localized amyloidosis), and +ve calcitonin immunostain)

○ Pt has high level of calcitonin which can lead to hypocalcemia

Fig - MTC biopsy. All the pink stuff seen is calcitonin amyloid.
32. Describe familial cases of MTC (HY). What's significance of RET oncogene (HY)?

- Often associated with MEN 2A or 2B phenotype. (MEN = muliple endocrine neoplasia)
- MEN 2A - often see MTC, pheochromocytoma and parathyroid adenomas

Endocrine Page 2.8

- MEN 2A - often see MTC, pheochromocytoma and parathyroid adenomas
- Men 2B - often see MTC, pheochromocytoma and ganglioneuroma of oral mucosa
- Familial cases of MTC is classically associated with mutation in RET oncogene
- If a person has RET oncogene, do a prophylactic thyroidectomy
33. Describe anaplastic carcinoma. How do you diagnose?
- Has the worst prognosis of all thyroid carcinomas
- It is undifferentiated and classically seen in old people
- Tumor has +ve keratin stain
- Often invades local structures leading to dysphagia or respiratory compromise.
- Clinically similar to Reidel fibrosing thyroidiyis but cancer is often seen in old people and

thyroidiyis in young females.

Fig - highly malignant cells in anaplastic carcinoma that don't resemble anything seen in thyroid
usually

Endocrine Page 2.9

15.8 Parathyroid

1. What is vitamin D? How do we get it?
- Two most imp vitamin D are vit D3 (cholecalciferol) and vit D2 (ergocalciferol)
- Cholecalciferol (D3) is made from 7-dehydrocholesterol by UV in skin
- Ergocalciferol (D2) is taken from food.
- Both of those are activated by liver in unregulated way, and kidney in regulated way

2. How does kidney activate vitamin D?
- Vit D itself is a prohormone. Kidney uses alpha 1 hydroxylase to make 1,25 OH D (active

vitamin D).

3. What are functions of PTH hormone?
- Chief cells make PTH that increase free serum calcium
- PTH acts on 3 main tissue

○ Stimulate kidney to increase vit D activation
○ Increase Ca absorption from kidney and phosphate excretion (phosphate excretion key

because it increases free Ca in blood)
○ Increase Ca and PO4 absorption from gut - this action is via Vit D
○ Increase osteoclast activity (PTH activates osteoblast which secretes M-CSF

(macrophage colony stimulating factor) which increase osteoclast differentiation and
activation) (HY)

4. What regulates blood PTH hormone?
- PTH release is highly sensitive to serum ca.
- Vitamin D also reduces PTH release
- Increase Ca ---> Gq and Gi activation. Gq increase calcium release in parathyroid cells --->

Decreases PTH synthesis. Gi decreases cAMP which reduces PTH synthesis
- Low Ca ---> Gs activation. Gs increases cAMP which increases PTH synthesis

5. What are functions of Vit D?
- Main function is to maintain bone mineralization
- Increase Ca and PO4 reabsorption in kidney
- Increase Ca and PO4 absorption in gut
- Decrease PTH secretion

6. What are function of calcitonin and phosphatonin?
- Tone down serum Ca and PO4
- Phosphatonins are important because intestinal absorption of phosphate is unregulated

Primary hyperparathyroidism
7. Explain primary hyperparathyroidism.
- Excess PTH; most common cause is PT adenoma (80%)
- Other causes - PTH hyperplasia, PTH carcinoma

8. Describe presentation of PT adenoma (i.e., symptoms of hypercalcemia).
- Benign; mostly asymptomatic
- If symptomatic

○ Nephrolithiasis - kidney stone (classic is calcium oxalate)
○ Nephrocalcinosis - example of metastatic calcification - Ca deposits in tubules
○ CNS disturbance - depression, seizure

Constipation, peptic ulcer, acute pancreatitis (HY) - think Ca as an enzyme activator that

Endocrine Page 3.1

○ Constipation, peptic ulcer, acute pancreatitis (HY) - think Ca as an enzyme activator that
activates pancreatic enzymes.

○ Osteitis fibrosa cystica - massive reabsorption of bone leading to fibrosis and cyst
formation

- Treatment - surgery

9. What are lab findings in primary hyperparathyroidism?
- Increase serum PTH
- High serum Ca
- Low serum phosphate (PTH increase phosphate excretion)
- High urine cAMP (HY)

○ PTH works in kidney via Gs to increase cAMP. Some cAMP gets to urine.
- High serum alkaline phosphatase (HY)

○ Alkaline phosphatase generates alkaline environment in bone so that new bone can be
laid down. Alk Phos is a sign of osteoblast activity. Remember that PTH first activates
osteoblast which in turn activates osteoclast. Osteoblast activation leads to high alk
phos.

Secondary hyperparathyroidism
10. What are some causes for 20 hyperparathyroidism?

- Most common is chronic renal failure (HY)
○ Decreased phosphate excretion --> reduced free calcium in blood as most of it is bound
to phosphate ---> increased PTH production and increased bone reabsorption

11. What are lab findings in 20 hyperparathyroidism?
- Increased PTH
- Decreased serum Ca (remember that the whole process is driven by high PO4. It binds to free
serum Ca and reduces it)
- Increased serum PO4
- Increased alkaline phosphatase (increased PTH leads to increase alk phos)

Hypoparathyroidism
12. What are causes of hypoparythoroidism?

- Autoimmune
- DiGeorge syndrome (failure of develop 3rd and 4th pharyngeal pouch. Parathyroids develop

from 3rd and 4th pharyngeal pouch).

13. What are its presentation - due to low Ca?
- Numbness and tingling (specially perioral)
- Muscle spasm (ex - when you put BP cuff on them or touch their face)
- Low serum Ca and PTH

Pseudohypoparathyroidism
14. What causes pseudohypoparathyroidism?

- Caused due to end organ resistance of PTH
- Hypocalcemia with increased PTH level (also see this is secondary hyperparathyroidism; but 20

hyperparathyroidism has increased serum phosphate levels too)
- Autosomal dominant form (mutation of Gs) associated with short stature and short 4th and

5th digit

Endocrine Page 3.2

15.9 Endocrine Pancreas

Insulin - major anabolic hormone. Upregulates GLUT4 receptors in muscle and fat. Increased
glucose leads to glycogen synthesis, fat synthesis, protein synthesis
Glucagon - major catabolic hormone. Causes gluconeogenesis from AA, lipolysis and
glycogenolysis.

1. Describe the anatomy of endocrine pancreas.
- Composed of cluster of cells called islet of Langerhans
- Single islet has many types of cells; each type producing one type of horome
- Insulin is made by B cells; lie in center of islet
- Glucagon is made by alpha cells.

Type 1 DM
2. Explain Type 1 DM
- Autoimmune destruction of B cells by T lymphocytes (type 4 hypersensitivity) - see inflammation
of islets
- Autoantibodies against insulin - can be seen years before disease
- Associated with HLA DR3 and DR4

3. What's presentation of type 1 DM?
- Classically seen in children
- Presentation (of insulin deficiency)

○ High blood glucose
○ Weight loss despite polyphagia (high hunger), low muscle mass - due to unopposed

catabolic action of glucagon
○ Polyuria, polydipsia, glycosuria
- Treatment - lifelong insulin

4. Explain mechanism of DKA (feared complication of type 1 DM)
- Excess serum ketoacids; often triggered by stress (ex-infection)
- Epinephrine increases glucagon that exacerbates lipolysis. Free fatty acids generated go to liver

and get converted to ketones.

5. What is presentation of DKA?
- Hyperglycemia (>300 mg/dl) - due to unopposed glucagon actoin
- Anion gap metabolic acidosis (from ketoacids)
- Hyperkalemia (HY)

○ insulin stimulates Na/K pump. Also, acidosis is compensated by exchanging H+ from serum
to K in cells. Much of the serum K will be lost in urine. So person has loss of total K from
body; but has hyperkalemia

- Kussmaul respiratin (to compensate for acidosis), dehydration (from diuresis), mental status
change, fruity breath

6. How do you treat DKA?
- Give fluids - to treat dehydration
- Insulin
- Give potassium - because when you give insulin, K will go inside the cells; also serum K goes down

as acidosis is treated

Type 2 DM
7. Explain type 2 DM.

Endocrine Page 4.1

7. Explain type 2 DM.
- End organ insulin resistance
- Risk factor - obesity; Obesity reduces insulin receptors (HY)
- Higher genetic predesposition compared to type 1 DM

8. Describe presentation of type 2 DM.
- Initially, see high insulin. Later on B cells get exhausted so see low insulin
- Histology shows amyloid deposition in islets

Fig - amyloid deposition in Islets in type 2 DM. Amyloid is made of amylin - a protein
produced with insulin.

9. What is presentation and diagnosis of type 2 DM?
- Polyuria, polydipsia, hyperglycemia, often clinically silent
- Diagnosis

○ Random glucose (>200 mg/dl)
○ Fasting glucose (>126 mg/dl)
○ Glucose tolerance test (>200/dl two hours after glucose load)

10. How do you treat type 2 DM?
- Weight loss and exercise first line
- Drugs
- Insulin

11. Describe hyperosmolar non-ketotic coma.
- MOA - High glucose levels (>500 mg/dl) leads to life threatening diuresis
- Don't see ketoacidosis because some insulin is present which prevents lipolysis and fat breakdown
- Hypotension
- Coma (due to osmolar effect in brain)

12. What are two major complications of diabetes? Give examples of diseases.(HY)
- Non enzymatic glycosilation (NEG) of vascular basement membrane
○ NEG of large and medium vessels lead to artherosclerosis - ex - peripheral vascular disease
leading to amputation
○ NEG of small vessel leads to hyaline arteriolosclerosis - ex - diabetic nephropathy (nephrotic
syndrome)
○ NEG of hemoglobin leads to HbA1c - long term marker of glycemic control
- Osmotic damage

Endocrine Page 4.2

- Osmotic damage
○ Some cells in body can take sugars without insulin
 Schwann cells - aldose reductase reduces glucose to sorbitol in Schwann cells. Sorbitol
leads to osmotic damage. Leads to peripheral neuropathy.
 Pericytes of retinal blood vessel - sorbitol cause osmotic damage and pericytes die.
Leads to anurysm of retinal blood vessel. Rupture leads to blindness.
 Lens - sorbitol build up leads to cataract.

13. What are some pancreatic endocrine tumor?
- MEN 1
○ Parathyroid hyperplasia and pituitary adenoma, pancreatic endocrine tumor
- Insulinoma -
○ Tumor makes insulin
○ Presentation-
 Mental status change due to severe hypoglycemia that is relieved by glucose
 Lab - Low glucose, high insulin, high C peptide (C peptide is made along with insulin)
- Gastrinoma
○ Gastrin induces parietal cells in stomach to make acid
○ Presentation
 Treatment resistant peptic ulcers (aka Zollinger Ellison syndrome)
 Ulcers can extend to jejunum
- Somatostatinoma
○ Somatostatin reduces acid production and contraction of gall bladder
○ Presentation
 Achlorhydria (low acid production in stomach)
 Cholelithiasis and steatorrhea (due to reduced bile release)
- VIPoma
○ Vasoactive intensinal peptide greatly stimulates secretion of water and electrolytes in
intestine, reduces gastric acid production.
○ Presentation
 Watery diarrhea
 Hypokalemia
 Achlorhydria

14. What are two proteins that are made together with insulin?
- Amylin - in type 2 DM, we see amyloid buildup due to amylin buildup
- C peptide - can be tested in blood to see if pt is overadminstering insulin

Endocrine Page 4.3

15.10-15.11 Adrenal Cortex and Adrenal Medulla

Crotex - hormones are made from cholesterol (cortex is yellow due to cholesterol)
Medulla- hormones made from tyrosine

1. What are three layers of adrenal?

Zona glomerulosa Mineralocorticoid (Aldosterone)
Zona fasciculata Glucocorticoid (Cortisol)
Zona reticularis Sex steroids

Pneumonic GFR for the zones.

2. Describe metabolism of cortisol.
 Transport

o 75% transported by transcortin (aka corticosteroid binding globulin) (made by liver)
o 15% bound to albumin
o 10% in free form
 Receptor - nuclear receptor. Present in all body cell
 Can bind strongly to mineralocorticoid receptor as mineralocorticoid itself.

3. How do you get hypokalemia from too much licorice ingestion?
 Cortisol is inactivated to cortisone in kidney tubules by 11-B-hydroxysteroid dehydrogenase type 2

(reverse reaction by type 1 dehydrogenase). Licorice inactivates the type 2 enzyme, leading to active
cortisol in kidney tubules.
 As cortisol has high mineralocorticoid action, it leads to potassium excretion in kidney tubules leading to
hypokalemia.

4. What are functions of glucocorticoids (called glucocorticoid because it increases glucose in blood)?
 Increased glucose output by liver and decrease glucose intake by muscle, adipose (to increase glucose

supply to brain and heart)
 Decreased insulin sensitivity
 Decreased immune activity via

o Decreased arachidonic acid production (due to inhibition of phospholipase A2)
o Low IL-2 production (IL2 important for proliferation of T cells)
o Low histamine production
 Increased alpha one receptor production and sensitivity to catecholamines (lack of cortisol causes
extreme vasodialation, extreme hypotension and death)
 Negative feedback to ACTH

5. How does adrenal insufficiency cause hypotension?
- ↓glucocorticoid (GC)  too much vasodialation
- ↓mineralocorticoid (MC) hypovolemia (too much Na and water wastage from kidney )

6. What are clinical features of Cushing’s syndrome (too much GC)?
- Muscle weakness (AA in muscles are used for gluconeogenesis) with thin extremities
- Moon faces, buffalo hump, truncal obesity (high glucose in blood leads to insulin release; insulin is an

anabolic hormone and leads to fat storage)
- Abdominal striae (cortisol impairs collagen synthesis; blood vessels in stomach ruptures leading to striae

formation)
- HTN (increased sensitivity and production of alpha 1 receptor)

Endocrine Page 5.1

- HTN (increased sensitivity and production of alpha 1 receptor) Adrenal gland size
- Osteoporosis Both atrophied
- Immune suppression One secreting cortisol big, other
atrophied
7. What are causes of cushings? Both large
Cause Both large
Exogenous cortisol (most common)
Primary adrenal adenoma, hyperplasia, carcinoma (aka cushing's
disease - 2nd most common)
ACTH secreting pituitary adenoma
Paraneoplastic ACTH secretion (ex - small cell carcinoma of lung)

8. How do you distinguish between cushing's due to ACTH made by pituitary vs pituitary made somewhere
esse (paraneoplastic)?

- Do a dexamethasone suppression test. ACTH produced by pituitary will go down but not the
paraneoplastic one.

9. What is presentation of hyperadlosteronism?
- Hypernatremia, HTN
- Hypokalemia, metabolic alkalosis
- Aldosterone causes principal cell of kidney to take Na and excrete K.

10. Describe features of primary hyperaldosteronism.
- Most commonly due to adrenal adenoma. Less common - hyperplasia and carcinoma
- High aldosterone and low renin

11. Describe features of secondary hyperaldosteronism
- Causes- fibromuscular dysplasia (classically seen in young woman where renal artery is stenosed),
atherosclerosis of renal artery
○ As kidney sees low blood flow, RAAS is activated leading to high aldo
- See high renin and high aldo

11. Describe cause of congenital adrenal hyperplasia (occurs in both androgen)
- Most commonly seen due to deficiency of 21- hydroxylase (required to make cortisol and aldo)
- Deficiency of cortisol leads to excess production of ACTH leading to hyperplasia of adrenals (remember
ACTH is a trophic hormone)
- Other causes - 11 hydroxylase and 17 hydroxylase deficiency (leads to low cortisol)

12. What is presentation of congenital adrenal hyperplasia?
- Excess sex steroids (hormone production shunted towards sex hormone production due to deficient 21-
hydroxylase)
o Clitoral enlargement
o Precocious (early) puberty in males
- Life threatening hypotension (cortisol deficiency)
- Hyponatremia, hypovolemia; hyperkalemia, acidosis (aldo deficiency)

13. How does 11 hydroxylase deficiency present in contrast to 21 hydroxylase deficiency?
- In 11 hydroxylase deficiency, we don't see effects of hypomineralocorticoid; but see effect of
hypocortisol and excess sex hormone
- Reason - Both 21 and 11 hydroxylase are required for cortisol production. 21 hydroxylase can produce
weak mineralocorticoid, and 11 hydroxylase is needed to make strong mineralocorticoid.

Endocrine Page 5.2

Adrenal insufficiency
14. What is presentation of Waterhouse-Friderichsen syndrome (acute adrenal insufficiency)?

- Commonly seen in kid with Niserria meningitis infection that causes DIC and then bilateral necrosis of
adrenal glands

- See massive hypotension

Fig - sac of blood adrenals classically seen in waterhouse friderichsen syndrome
15. What are causes of chronic adrenal insufficiency?

- Autoimmune (most common cause in developed world)
- TB (most common cause in developing world)
- Metastatic carcinoma to adrenals (lung cancer loves to go to adrenal)
16. What are presentation of chronic adrenal insufficiency?
- Hypotension (low cortisol)
- Hyponatremia, hypovolemia; hyperkalemia, acidosis (aldo insufficiency)
- Weakness
- Hyperpigmentation (HY) - ACTH is made from POMC. POMC also induces melanin synthesis. High ACTH

means high POMC which leads to high melanin synthesis - classically seen in oral mucosa and skin. - only
see in 10 adrenal insufficiency.
- Vomiting and diarrhea (low cortisol)
17. Describe pheochromocytoma (tumor of adrenal medulla)
- Medulla is made of neural crest derived chromaffin cells (HY)
- Pheo is tumor of chromaffin cell
- Classic finding - brown tumor (because chromaffin cells are brown)

Fig - pheochromocytoma. Yellow parts seen in left and right are adrenal cortex.
18. What are presentation of pheochromocytoma?

- Episodic HTN, headache, palpitation
- Orthostatic hypotension may be seen - because alpha receptors are sensitized to high levels of

Endocrine Page 5.3

- Orthostatic hypotension may be seen - because alpha receptors are sensitized to high levels of
catecholamines

- Diagnosis -
o increased serum metanephrines
o Increased urine metanephrines and VMA
o Epi and NE are metabolized to metanephrine and normetanephrine respectively. MAO converts
both of them to VMA.

- Treatment - surgery (HY - give phenoxybenzamine (irreversible alpha 1 blocker) before surgery because
mechanical stress of adrenal can leak out epi and NE giving pt HTN and too much bleeding).

19. What are rule of 10's involving pheo?
- 10% bilateral
- 10% familial
- 10% malignant
- 10% located outside adrenal (HY - a common site is urinary bladder - classic presentation is a patient
who experiences headaches and palpitation while urinating).

20. What are associations of pheo?
- MEN 2A (MTC, pheo and parathyroid adenoma) and
- 2B (MTC, pheo and mucosuloganglio neuroma esp in oral mucosa). MTC can kill pt so people with MEN
go prophylactic thyroidectomy. Ret oncogene linked to MTC.
- VHL disease (autosomal dominant mutation of von hippel lindau tumor suppressor gene - increased risk
of hemangioblastoma of cerebellum, renal cell carcinoma, pheo)
- NF type 1

21. Why don't you give beta blocker in pheo to control HR?
- B2 is a vasodialator. B1 increases HR. If B blocker is given, we have uncontrolled alpha action (very
severe vasoconstriction).

Endocrine Page 5.4

Chapter 16: Breast Pathology

16.1 Introduction

1. Describe the anatomy and histology of breast.
- Anatomy:

○ Breast can develop anywhere along the milk line (a straight line from vulva to axilla)
○ In females, lobules and ducts are present in highest density in upper lateral part of breast
○ In males, lobules and ducts are present in highest density in subaerolar area
○ Estrogen and progesterone cause hyperplasia of breast lobules
- Histology:
○ Terminal duct and lobular unit is the functional unit of breast. Lobules make milk and ducts

drain them
○ Lobules and ducts are lined by two cell layers:

 Luminal cell layer: columnar epithelial cell that makes milk in lobules
 Myoepithelial cell layer: Outer layer; contracts to expell milk outside
2. What is galactorrhea? What are its causes?
- Galactorrhea is milk production outside pregnancy
- Causes:
○ Nipple stimulation
○ Prolactinoma
○ NOT A SIGN OF CANCER

Breast Page 1.1

16.2 Inflammatory Conditions

1. Describe the following inflammatory conditions of the breast.

Cause Presentation Treatment

Acute - Staph Aureus infection - Erythematous breast - Continue
mastitis - Associated with breast feeding (fissures - Purulet nipple drainage
develop in nipple and bacteria enter) discharge - Dicloxacill
- May have abscess in

Periductal - Usually seen in smokers. Smoking causes - Subareolar mass with
mastitis relative Vit a decifiency. Vit A deficiency - nipple retraction - due
causes squamous metaplasia of periductal to inflammation and
cells. Cells produce keratin and block the fibrosis
duct resulting inflammation

Mammary - Chronic inflammation that causes dilation - Periareolar mass with
duct ectasia (ectasia) of subareolar duct green-brown nipple
(dialation) discharge
- Plasma cells on biopsy

Fat necrosis - Usually related to trauma - Mass on physical exam
or abnormal
calcification on
mammography (due to
saponification)
- Calcification and giant
cells on biopsy

Breast Page 2.1

16.3 Benign Tumors and Fibrocystic Changes

1. Describe the following benign tumor and fibrocystic changes in the breast.

Epidemiology Presentation

Fibrocystic Most common change in premenopausal - Presents as vague irregularity
change women (hormone mediated) - seen in 30-60% (lumpy breast) in upper outer
of women quardant
- Cyst look blue-dome on gross
exam

Fig: fibrocystic change presents as fibrosis of
stromal cells and cystically dilated ducts

Intraductal Classically seen in premenopausal women - Bloody or serous nipple
papilloma discharge
- Usually present in one of the
main lactiferous duct below
areola and may cause nipple
retraction

Fig: intraductal papilloma (mass has both - Well circumscribed mobile
epithelial and myoepithelial layers) marble like mass - move freely
(contrast to infiltrative ductal
Fibroadenoma - Most common benign neoplasm of breast
(classically seen in premenopausal woman) -
hormone sensitive - mass grows during

Breast Page 3.1

hormone sensitive - mass grows during (contrast to infiltrative ductal

pregnancy and maybe painful in menstruation carcinoma that's immobile)

cycle - Benign - 1.5-2x increased risk of

- Growth of fibrous part squeezes the lumen of cancer (FA)

duct

Fig: Fibroadenoma (growth of both lobular
and stromal cells)

Phyllodes Fig: gross speciman shows well demarked, - Fibroadenoma like tumor but
tumor capsulated tumor much larger with overgrowth of
(phyllodes = fibrous part
leaflike) Classically seen in postmenopausal woman - Leaf like projection on biopsy
(tumor of stromal cell - cells
between lobules)
- Maybe malignant in some cases
- Most common in 5th decade

Fig: fingerlike projection of Phyllodes tumor
(stromal tumor)
- Only phyllodes tumor is mainly seen in postmenopausal woman and maybe malignant. All others
are seen mainly in premenopausal woman and not usually malignant

Breast Page 3.2

2. What are the different types of fibrocystic changes and their associated breast cancer risk?

Breast cancer risk Presentation

Fibrous, cysts and No increased risk
apocrine metaplasia

Ductal hyperplasia and 2x increased risk in Sclerosing = hard (fibrous); adenosis = too
sclerosing adenosis
both breasts many glands; calcification maybe seen

Atypical hyperplasia 5x increased risk in Hyperplasia maybe lobular or ductal
both breasts

3. How do you distinguish intraductal papilloma from papillary carcinoma of breast?

Intraductal papilloma Papillary carcinoma

Both present as bloody nipple discharge

More common in premenopausal women As it's cancer, its more common in
postmenopausal women

Papillary growth has both epithelial and Papillary growth has epithelial cells but lacks
myoepithelial cells myoepithelial cells

Breast Page 3.3

16.4 Breast Cancer

1. What are the risk factors for breast cancer?
- Risk factors are associated with estrogen exposure

○ Female gender (female:male = 100:1 for breast cancer incidence)
○ Age - cancer usually seen in postmenopausal woman with exception of hereditary breast cancer
○ Early menarche/late menopause (increases estrogen exposure)
○ Obesity (fat cells converts testosterone to estrogen)
○ Atypical hyperplasia
○ First degree relative with breast cancer
○ Race - AA at more risk
○ BRACA +ve (BRACA 1 = risk of ovarian cancer and triple neg breast cancer; BRACA 2 = breast cancer in males)

2. What are the characters of the following types of breast cancer?

Ductal Histology Mass? Remarks?
carcinoma in - No mass
situ - Cell proliferate in duct without invading basement membrane
- Histologic subtypes present:

• Comedo type: high grade cells with necrosis in duct with
calcification

Invasive ductal Fig: DCIS - note cellular proliferation, necrosis and centrally located Fig: DCIS mammography
carcinoma calcification
- Rock hard immobile mass - grossly see
- MOST COMMON INVASIVE CARCINOMA OF BREAST - >80% of cases classic 'stellate' appearance
- Invasive cancer that produces duct like structure in desmoplastic stroma - Most common of all breast cancer
- Subtypes: - Inflammatory has worst prognosis; others
have relatively good; Invasive lobular has
• Tubular carcinoma: better prognosis than invasive ductal.
○ has well differentiated ducts without myoepithelial layer in
desmoplastic stroma Fig: 'stellate' invasive ductal carcinoma
○ Good prognosis

• Mucinous carcinoma:
○ ducts in abundant extracellular mucin
○ Good prognosis

• Medullary carcinoma:
○ high grade ductal cells associated with lymphocytes and
plasma cells
○ Increased incidence of BRCA1 carriers
○ Good prognosis

• Inflammatory carcinoma -
○ carcinoma in dermal lymphatics
○ Poor prognosis (tumor already in lymph)
○ Presents as inflamed, swollen breast due to blockage of
lymphatics - orange peel appearance; can be mistaken for
acute mastitis

Breast Page 4.1

Fig: Peau d'orange (orange peel)
appearance of inflammatory carcinoma

Fig: Tubular carcinoma (left); mucinous carcinoma (right)

Lobular Fig: medullary carcinoma (left); inflammatory carcinoma (right) - No mass, no calcification - usually
carcinoma in discovered incidentally
situ - Cells proliferate in lobules without invading basement membrane - Often bilateral
- Often multifocal and bilateral
- Characterized by dyscohesive cells lacking E-cadherin adhesion protein
- Treatment:

• Tamoxifen (to reduce risk of carcinoma)
• Follow up closely because it can progress to invasive carcinoma

Invasive lobular - Cells characteristically grows in single file (aka Indian file) and may show - Often bilateral and multiple lesions in
same location
carcinoma signet ring morphology - cells don't make duct because they lack E- - Better prognosis than invasive ductal
carcinoma
cadherin - Associated with lobular carcinoma in situ
in 90% of cases
- Usually bilateral - Has diffuse invasive pattern of spread so
difficult to detect by physical or radiologic
exam

Fig: Small runs of invasive lobular carcinoma (arrows) with two adjacent
foci of LCIS.

3. What are the prognostic factors for breast cancer?
- TNM staging

○ Metastasis is most important prognostic factor but pt present early so not very useful
○ Spread of tumor to axillary lymph nodes (N) is most useful prognostic factor - Sentinel lymph node biopsy used to assess axillary

lymph nodes

4. What is sentinel lymph node biopsy?
- Many years before, doctors use to take out all lymph nodes in axilla to check for spread of breast cancer. In many patients, there was no

Breast Page 4.2

- Many years before, doctors use to take out all lymph nodes in axilla to check for spread of breast cancer. In many patients, there was no
spread and they had to suffer upper extremity edema due to lack of lymph nodes

- Then doctors started to inject dye in tumor and check which lymph nodes in axilla the dye moved to. If the lymph nodes with dyes didn't
had metastasis, the doctors didn't take out all the lymph nodes. If the nodes had metastasis, they would then proceed to take out all lymph
nodes. This process is called sentinel lymph node biopsy.

5. What are the predictive values of breast cancer treatment?
- Imprtant predictive values of treatment are presence of absence of overexpression of estrogen receptor (ER), progesterone receptor (PR),

and HER2/neu receptor. (HER2/neu are receptors in RAS/MAPK pathway).

Overexpression of ER, PR (nuclear receptor) Good response to antiestrogenic agents (ex-
tamoxifen)

Overexpression of Her2/neu receptor (cell surface receptor) Good response to trastuzumab (anti HER2
receptor Ab)

Triple negative receptor (none of above overexpressed) - usually seen in African Poor pharmacological prognosis
American women

6. What is Paget's disease of nipple?
- Extension of ductal carcinoma in situ to lactiferous ducts and skin of nipple producing rash. Paget cells are present.

Fig: Paget disease of nipple 10% of breast cancer cases
Hereditary breast cancer
- Seen in premenopausal cancer
Epidemiology - Presence of multiple tumor
Presentation - Having multiple first degree relative with breast cancer

Mutations - BRCA1- breast (medullary carcinoma - type of invasive ductal carcinoma) and ovarian carcinoma
(serous carcinoma)
Value of prophylatic bilateral - BRCA2 - breast carcinoma in males
mastectomy
- Decreases risk of carcinoma but not to zero

Male breast cancer - 1% of all breast cancers
Epidemiology
Common type - Invasive ductal carcinoma
Presentation
- Subareolar mall in older males (most breast tissue in males is in subareolar area - in females, it's in upper outer
Genetic quadrant of breast)
associations - May have nipple discharge

- Klinefelter syndrome (XXY)
- BRCA2 mutations

Breast Page 4.3

Chapter 17: Central Nervous System
Pathology

17.1 Developmental Anomalies

Neural tube defects

Defn - Incomplete closure of neural tube due to folate deficiency prior to conception. Two types

Anencephaly Spina bifida

- Absence of skull and brain - Failure of posterior vertebral arch to close

- Results in polyhydramnios as fetal - Types:
swallowing of amniotic fluid is impaired a. Spina bifida occulta (asymptomatic)-
- Vertebra is not fused because the plates of spinal arch can't

fuse because neural tube didn't close properly
- Asymptomatic; dimple of patch of hair overlying vertebral
defect

b. Spina bifida - cystic protrusion of underlying tissue
1. Meningocele - meninges protrude
2. Meningomyelocele - meninges and spinal cord protrude

Detecti - Can be detected by elevated alpha-fetoprotein (AFP) in amniotic fluid and maternal blood.
on - AFP most abundant protein in young fetus blood (albumin of fetus) - made by fetal liver and yolk sac.

- AFP elevated in other cases too - hepatocellular carcinoma, liver metastasis, yolk sac tumor, germ cell tumor.

Anatom - Neural plate invaginates early in gestation to make neural tube
y - Walls of neural tube - makes CNS

- Hollow lumen of neural tube - makes ventricles and spinal cord canal
- Neural crest - makes peripheral nervous system

Neurology Page 1.1

Cerebral duct stenosis
Defn - Stenosis of cerebral aqueduct (of sylvius) - connects 3rd and 4th ventricles; leads to
hydrocephalous
- CSF is made by choroid plexus lining the ventricles
Epid - MOST COMMON CAUSE OF HYDROCEPHALOUS IN NEWBORNS

- CSF leaks from 4th ventricle to subarachnoid space via foramen of Magendie
(middle) and foramen of Luschka (lateral)
Dandy walker malformation
Defn - Congenital failure of cerebellar vermis to develop so that 4th ventricle is massively
dialated and cerebellum is absent; often accompanied by hydrocephalous
- Presents as hydrocephalous, increased ICP and motor problem.
- Associated with other abnormalities of CNS and malformation of heart, limbs etc.

Neurology Page 1.2

Arnold-Chiari malformation
Defn - Congenital downward displacement of cerebellar vermis and tonsils through foramen
of magnum, leading to obstructive hydrocephalous
- Often associated with meningomyelocele - cerebellum is pulled downward

Neurology Page 1.3

17.2 Spinal Cord Lesions

Seringomyelia - Cystic degeneration of spinal cord usually on C8-T1 that affects the spinothalamic
Defn (anteriolateral) pathway and later on affects anterior horn (motor neurons) and
lateral horn (SANS)
- Typically spares dorsal column pathway (fine touch and position)

Presentati - Sensory loss of pain and temperature in upper extremities and 'cape like'
on distribution (anterior white commissure of spinothalamic tract)

- Muscle atrophy and weakness (anterior horn damage)
- Horner's (lateral horn - hypothalamospinal tract damage)
Poliomyelitis
Defn - Anterior horn neurons damage due to poliovirus infection
Presentation - Presentation based on lower motor neuron sign

• Flaccid paralysis with muscle atrophy
• Babinski -ve
• Impaired reflexes
Werding-Hoffman disease
Defn - AR inherited degeneration of anterior motor horn
- Presents as floppy baby and death within a few years after birth

Neurology Page 5.1

Amotrophic lateral sclerosis (ALS)

Defn - Degeneration of both upper and lower motor neuron of corticospinal tract

Cause - Most cases are sporadic
- Some familial cases due to mutation in zinc-copper superoxide dismutase mutation
(SOD1) - causes free radical injury in neurons

Presentati - Lower motor neuron signs:
on • Flaccid paralysis and muscle atrophy

• Fasciculations
• Negative Babinski
- Upper motor neuron signs:
• Spastic paralysis with hyperreflexia
• Increased muscle tone
• +ve Babinski
- Sensory system intact (distinguish from syringomyelia)
- Atrophy and weakness of hand early sign

Fredreich ataxia

Defn - Degenerative disorder of cerebellum and spinal cord due to unstable trinucleotide
repeat (GAA) in frataxin gene (autosomal recessive)

Pathophys - Frataxin gene imp for mitochondrial iron regulation; loss results in iron buildup with
free radical damage

Presentati - Loss of multiple spinal tracts:
on • Loss of vibration and proprioception

• Muscle weakness in lower extremities
• Loss of deep tendon reflex
- Presents in early childhood; pt are wheelchair bound in few years

Associatio - hypertrophic cardiomyopathy
n

Neurology Page 5.2

17.3 Meningitis

Defn - Inflammation of leptomeninges (arachnoid and pia)
Cause
Neonates - Group B strep (no 1), E. coli, Listeria, H flu (non-vaccinated
infants)

Teens and adults - N. meningitis, Strep pneumo

Immunecompromise - Fungi (cryptococcus
d

Viral - Most common is coxsackie (feco-oral transmission; kids)

Presentation - Classic triad of headache, fever and nuchal rigidity
- Photophobia and vomiting
- Altered mental status may be present

Diagnosis - Lumbar puncture
• SC ends at L2; put needle between L4 and L5 - level of iliac crest; cauda equina
continues to S2

CSF findings Cells Glucose Protein

Bacteria Neutrophils Low ?

Virus Lymphocytes Normal ?

Fungal Lymphocytes Low ?

Complicatio - Commonly seen in bacterial meningitis
ns • Hydrocephalus, hearing loss and seizures - due to fibrosis

• Death - due to herniation and cerebral edema

Neurology Page 6.1

17.4 Cerebrovascular Disease

Stroke - No. 3 cause of death in USA
Epdm - Neurons are susceptible to ischemia and undergo necrosis within 3-5 mins

Types

Global cerebral ischemia

Etiologi - Low perfusion (ex- atherosclerosis)
es - Acute decrease in blood flow (ex - cardiogenic shock)

- Chronic hypoxia (ex- anemia)
- Repeated episodes of hypoglycemia (ex- insulinoma)

Present - Presentation based on duration and magnitude of insult
ation

Ischemic stroke (focal cerebral ischemia)

Defn - Regional ischemia that causes focal neurological defects lasting >24 hours
- If symptoms last <24 hours, it's called transient ischemic attack (TIA)

Subtype Thrombotic Embolic Lacunar
s
- Due to rupture of artherosclerotic plaque - Due to emboli from - Due to hyaline
Cause left heart (ex- a-fib) arteriolosclerosis
(complication of HTN
and diabetes)

Location - Mostly at branch points (ex- bifurcation - Usually middle cerebral - Mostly lenticulostriate

of internal carotid and middle cerebral artery vessels

artery at cirlce of Willis)

Presentat - Pale infarct at periphery of cortex - Pin point hemorrhagic - cause small cystic
ion infarct over triangular infraction

Neurology Page 3.1

ion infarct over triangular infraction
area - If internal capsule
involved --> pure motor
stroke
- If thalamus involved -->
pure sensory stroke

Outcom - Liquefactive necrosis

e 12-24 - Eosinophilic change in neurons (red neurons)

hours - Necrosis after 24 hours

1-3 days - Neutrophil infiltration
3-7 days - Microglial infiltration
2-3 weeks - Gliosis (reactive astrocytes line space)

HEMORRHAGIC STROKE
Intracerebral hemorrhage

Defn - Bleeding in brain parenchyma - classically due to rupture of Charcot-Bouchard micro-aneurysm of
lenticulostriate vessels in Basal ganglia (contrast to ischemic lacunar stroke of lenticulostriate vessels due
to arteriolosclerosis)

Present - Headache, nausea, vomiting, and eventual coma
ation
Preventi - HTN treatment will reduce incidence by half

Neurology Page 3.2

Preventi - HTN treatment will reduce incidence by half
on

Subarachnoid hemorrhage
Defn - Bleeding to subarachnoid space (blood vessels are outside pia but inside the arachnoid layer)

Presentation - Worst headache of life (aka thundercloud headache) with nuchal rigidity

Cause - Rupture of berry aneurysm (85% of cases)
• Most commonly located in branch point of anterior communicating artery
• Aneurysm lacks media layer

- AV malformation
- Anticoagulated state

Berry aneurysm - Marfan syndrome

association - Dominant polycystic kidney disease

Neurology Page 3.3

17.5 Trauma

Subdural and epidural hematoma

Epidural hematoma Subdural hematoma

Defn - Collection of blood between dura - Collection of blood between below dura
and skull

Cause - Classically due to rupture of - Due to tearing of bridging veins that lie
middle meningeal artery from between dura and arachnoid - commonly in
trauma to temporal bone elderly (have atrophied brain) with trauma

Presentati - Lucid interval may precede - Progressive neuro sign (takes months for

on neurologic sign (so disease called bleeding to accumulate)

talk and die disease)

Imaging - Lens shaped lesion on CT - Crescent shaped lesion on CT

Cause of - Herniation Fig: red arrow- acute; blue arrow - chronic
death hemorrhage

- Herniation

Herniation (displacement of brain tissue due to mass issue of increased ICP)

Tonsilar herniation Subfalcine herniation Uncal herniation

Defn - Cerebellar tonsils - Cingulate gyrus - Temporal lobe uncus herniates
herniates under
foramen magnum herniates under falx under tentorium cerebeli

cerebri

Presenta - Compression of - Compression of - CN3 palsy - eye moving down and
out and dialated pupil
tion brainstem can lead to anterior cerebral - Posterior cerebral artery
compresion - infraction of posterior
cardiopulmonary artery leads to cerebral arery (contralateral
homonymous hemianopsia)
arrest infraction - Rupture of paramedian artery -
Duret (brainstem) hemorrhage

Neurology Page 7.1

17.6 Demyelinating Disorders

Defn - Disease where myelin is damaged; axons are generally preserved

Myelin types - Oligodendrocytes - myelinate CNS; single cell myelinate multiple
neurons
- Schwann cells - myelinate PNS; single cell myelinate single neuron

Leukodystrophy

Defn - Inherited mutation in enzymes necessary to produce or maintain
myelin

Metachromatic - MOST COMMON LEUKODYSTROPHY
leukodystrophy - Deficiency of arylsulfatase. Sulfatides can't be degraded and

accumulate in lysosome of oligodendrocytes
- Autosomal recessive

Krabbe disease - Deficiency in galactocerebrosidase. Galactocerebroside accumulates
in m
- Autosomal recessive

Adrenoleukody - Impaired addition of coenzyme A to long-chain fatty acids (X-linked

strophy defect)

- Accumulation of fatty acids damages adrenal glands and white

matter of brain

Multiple sclerosis

Defn - Autoimmune destruction of CNS myelin and oligodendrocytes

Epid - Most common chronic CNS disease of young adults (20-30 years)
- More common in women and who live far away from equator

Genetics - Associated with HLA-DR2

Diagnosis - MRI reveals white matter demyelination
- Lumbar puncture:

• Increased lymphocytes and immunoglobulin
• oligoclonal IgG bands on high resolution electrophoresis
• Myelin basic protein

Neurology Page 8.1

Presentation - Relapsing and remitting neurological features (comes and goes)
• Vision:
○ Optic nerve damage - blurred vision in one eye
○ MLF damage - internuclear opthalmoplegia
• Hearing:
○ Vertigo and scanning speech (like drunk)
• ANS:
○ Bowel, bladder, and sexual dysfunction
• Spinal cord:
○ Lower extremity loss of sensation and weakness
• Cerebral white matter:
○ Hemiparesis or unilateral loss of sensation

Treatment - Acute attack with high dose steroids
- Long term treatment with interferon beta slows disease progression

Subacute sclerosing panencephalitis (Dawson disease)

Presentati - Progressive, debilitating encephalitis that leads to death caused by
on persistent infection of brain by measles virus

- Primary infection occurs in infancy; neuro signs arise 6-15 years later
- Initially presents as dementia, personality alterations, and loss of
movement control. Slowly progresses to speech loss of speech, loss of
ability to walk and dysphagia. Then, pt will be blind, mute, loss bodily
functions and be in vegetative stage and/or comatose and evenually die.
- Viral inclusions in neurons (gray matter) and oligodendrocytes (white
matter)

Progressive multifocal leukoencephalopathy

Defn - Rapidly progressive neurologic signs (vision loss, weakness, dementia and
eventually death in few months) caused due to JC virus damage of
oligodendrocytes (mainly during immunesuppression - AIDS, Rituximab, or
leukemia)

Imaging

Fig: multifocal white mater damages seen on T2 MRI (water is bright)

Neurology Page 8.2

Central pontine myelinolysis

Defn - Focal demyelination of pons due to rapid correction of hyponatremia

- Increasing Na concn too fast from low to high - makes your pons die

- From high to low - makes your brain blow

Presentation - Acute bilateral paralysis (locked in syndrome)

Neurology Page 8.3

17.7 Dementia and Degenerative Disorders

1. What are some basic findings in neurodegenerative diseases?
• Characterized by loss of neurons in gray matter
• Accumulation of intra and/or extracellular proteins
• Cortex degeneration: dementia; brainstem and basal ganglia degeneration: movement disorders
• Increased incidence with age

Alzhimers
2. What is clinical presentation of Alzhimer's (no. 1 cause of dementia)?

• Begins with short term memory loss and then long term memory loss
• Loss of motor skills and language
• Change in behavior and personality
• Pt become mute and bed ridden; infection is common cause of death
• Focal neurologic defect in late stage

3. What are the sporadic and familial etiologies of Alzhimers?

Mutation

Sporadic (95% of cases) • Seen in elderly • APO E epsilon 4 allele = increased risk
• APO E epsilon 2 allele = decreased risk

Familial cases (5% of cases) • Early onset • Presenilin 1 and 2 mutation
• Down's syndrome (dementia seen around 40)

4. What are gross and microscopic findings in alzhimers?
• Gross:
○ Cerebral atrophy and dilation of ventricles
• Microscopic
○ extracellular AB amyloid deposits
▪ Neuritic plaques ( A-Beta amyloid deposits with entangled neuritic process) (neuritic
process - dendrites and axon)
▪ cerebral amyloid angiopathy - A-Beta amyloid plaques deposit around vessels -
increases risk of hemorrhage
○ Intracellular neurofibrillary tangles (tuft of hyperphosphorylated tau protein): tau is
microtubule associated protein
○ Loss of cholinergic neurons in nucleus basalis of Myenert

Fig: Neuritic plaques (left) and neurofibrillary tangles (tau tangle) on right
5. How are A-beta (AB) amyloid plaques formed?

• AB amyloid is made from amyloid precursor protein (APP) encoded by chromosome 21. If APP
undergoes beta cleavage instead of normal alpha cleavage, AB amyloid is fomed.

• AB amyloid formation increases due to mutation in APP or trisomy 21.

Neurology Page 4.1

• AB amyloid formation increases due to mutation in APP or trisomy 21.

6. How is alzhimer's diagnosed?
• Clinically: diagnosis of exclusion
• Histology at autopsy or biopsy

Vascular dementia
7. Describe vascular dementia?

• 2nd most common cause of dementia
• Occurs due to multifocal white matter infraction
• Associated with HTN, artherosclerosis and vasculitis (they decrease blood flow to brain resulting in

infraction)
Frontotemporal dementia (pick disease)
8. What is clinical presentation of frontotemporal dementia (Pick disease)?

• Early language (termporal) and behavioral (frontal) difficulties which progresses to dementia
• Hallucination
• REM disturbances
• Personality change
• Usually seen in 40-50 year old (can be confused with midlife crisis)
9. What are biopsy findings of Pick disease?
• Round aggregate of Tau protein (compare to neurofibrillary tangle of Alzhimer's which is

triangular shaped)
Parkinson's and dementia with lewy bodies
10. What are biopsy finding of parkinson's disease?

• Loss of dopaminergic neurons in substantia nigra (part of basal ganglia) (compared to losing
neurons everywhere in Alzhimer's) (damage of negrostriatal pathway - used dopamine to initiate
movement)

• Lewy bodies (intracellular round, eosinophilic inclusions of alpha-synuclein) in affected neurons

Fig: Lewy bodies composed of alpha-synuclein
11. What are clinical presentation of Parkinsons?

• TRAP with dementia in late stage:
• Tremor (pill rolling tremor at rest that disappears with motion)
• Rigidity (cogwheel in extremities)
• Akinesia/bradykinesia (expressionless face:hypomimia, slowing of voluntary movement)

Neurology Page 4.2

• Akinesia/bradykinesia (expressionless face:hypomimia, slowing of voluntary movement)
• Postural instability and shuffling gait
11.5 Describe the pathophysiology of Parkinson's.
(add picture from karen's book)
12. What chemical exposure is associated with parkinsons?
• MPTP (a chemical used to cut illegal drugs)
• Most commonly, parkinson's is idiopathic.
13. What is biopsy and presentation of dementia with lewy bodies?
• Biopsy: presence of lewy bodies in cortex (parkinson's has lewy bodies in substantia nigra)
• Presentation: parkinsonian features, hallucinations
• Think dementia with lewy bodies as parkinson's disease with early onset dementia (within 1 year).
Huntingtons disease
14. What is genetic features of Huntington's disease?
• Autosomal dominant disorder (chro 4) with expanded trinucleotide repeat (CAG - glutamate) in

huntington gene
• Damage to GABAergic neurons in caudate nucleus (GABA = inhibitory)
• See anticipation (expansion of repeat during spermatogenesis causes this) - early onset of disease

with each generation (anticipation)

Fig: C is caudate (makes head that ends at lateral ventricle floor), P is putame. C+P = striatum
(called striatum because there's stripe running in between C and P).

Neurology Page 4.3

Fig: Cross section of huntington's pt brain showing small caudate that leads to hydrocephalus ex
vaculo (hydrocephalous due to loss of brain mass)

15. What is presentation of huntington's disease?
• Average age of presentation: 40
• Presents with chorea and progresses to dementia and depression

16. What is common cause of death in huntington's disease?
• Suicide

Normal pressure hydrocephalous
17. What is presentation of normal pressure hydrocephalous? How can you improve symptoms?

• Can causes dementia (idiopathically)
• Increased CSF leading to dilation of ventricles - causes stretching of corona radiata (nerve fibers

runing at side of ventricles).
• 3 W's caused due to stretching of corona radiata-

○ wet (urinary incontinence)
○ Wobbly (gait disturbance)
○ Wacky (personality changes)
• Symptoms improve with lumbar puncture. Treatment is VP shunt (ventricle-peritoneum shunt)

Spongiform encephalopathy
18. What is pathophysiology of spongiform encephalopathy?

• PrPc is normal CNS protein which is in alpha helical structure. It's converted to PrPsc which is in
beta pleated shape.

• PrPsc is congo red +ve (amyloid).
• PrPsc is resistant to damage by autoclave or sterilization or by proteases. Also, it can convert other

PrPc to PrPsc.

19. What are biopsy findings in spongiform encephalopathy?
• Intracellular vacuoles (called spongiform changes)

Neurology Page 4.4

Fig: Spongiform changes (intracellular vacuoles)
19.5. What are etiologies of spongiform encephalitis?

• Sporadic (idiopathically)
• Inherited - ex - fatal familial insomnia
• Transmitted -ex - transplant of cornea

20. Describe etiology and presentation of Creutzfeldt-Jakob disease (CJD)?
• Most common spongiform encephalopathy
• Etiology: mostly sporadic. Rare: contact with prion-infected human tissue (human growth
hormone, cornea transplant)
• Presentation:
○ Rapidly progressing dementia (weeks-months)
○ Ataxia (cerebellar changes)
○ startle myoclonus (involuntary muscle contraction with minimum stimulation)
○ Periodic sharp waves on EEG (HY)
○ Death usually <1 year

21. What is familial fatal insomnia?
• An example of spongiform encephalopathy with severe insomnia and exaggerated startle
response.
• Occurs via inheritance of mutation

22. What is variant CJD?
• CJD that arises in exposure to bovine spongiform encephalopathy (mad cow)
• Seen in younger people
• Other stuff is exactly similar to CJD

Neurology Page 4.5

17.8 CNS Tumors

Adult (supratentorial) Kid (infratentorial)

Astrocytes - Glioblastoma (M) - most common malignant Pilocytic astrocytoma (B) - most common
tumor in adults 10 brain tumor in kids

Oligodendrocytes - Oligodendroglioma (M) -

Ependymal cells (line - Ependymoma (M)
ventricles)

Neurons - Medulloblastoma (M) (neural ectoderm
tissue)

Meninges - Meningioma (B) (females mainly) - most common
10 brain tumor in adults

- Schwannoma (B) - Craniopharyngeoma (B)

B = benign; M = malignant

Adult tumors
1. Glioblastoma multiforme (GBM)

Defn - Malignant tumor of astrocytes

Epid. - Most common primary malignant brain tumor in adults

Presentatio - Often crosses corpus callosum (so called butterfly glioma)
n - Histoogy shows necrotic center with pseudopallisading tumor cells and (pallisade - wall).

Psuedopallisade = fuzzy wall (kiwi seed look like)
- Tumor cells are GFAP +ve (stains for glial cells)

Fig: butterfly glioma (left); pseudopallisading tumor cells (middle); GFAP stain on right
Prognosis - Poor prognosis; one of rare brain tumors to metastasize easily
2. Oligodendroglioma
Defn - Malignant tumor of oligodendrocytes
Presentation - Calcified tumor often involving frontal lobe

- May present as seizures
- Histology shows 'fired egg' appearance of tumor cells

Neurology Page 2.1

3. Meningioma

Defn - Benign tumor of arachnoid cells

Epid. - Most common 10 brain tumor in adults
- More common in women because tumor expresses estrogen receptors

Presentation - Histology:
• Whorled pattern of cells
• Psammoma bodies may be present

- Seen as round mass attached to dura on imaging - can cause seizure by compression

Fig: psammoma bodies (left); cellular whorls (middle); gross (right)

4. Schwannoma
Defn - Benign tumor of schwann cells that involves cranial or spinal nerves
Cause - If bilateral, associated with neurofibromatosis type 2
Features - If present within the cranium, most frequently involves CN 8 (presents as loss of hearing and tinnitus)
- Tumor cells S-100 +ve

Fig: schwannoma of median nerve (right)

Neurology Page 2.2

Fig: schwannoma of median nerve (right)

Kids tumor

1. Pilocytic astrocytoma

Defn - Benign tumor of astrocytes

Epid. - Most common 10 brain tumor in kids

Presentati - Imaging: cystic lesion with mural nodule in cerebellum
on - Histology: Rosenthal fibers (thick eosinophilic corkscrew process of astrocytes) and eosinophilic

granular bodies; GFAP +ve tumor cells

2. Ependymoma

Defn - Malignant tumor of ependymal cells usually seen in 4th ventricle

Presentati - Biopsy:
on • perivascular pseudorosette is characteristic (pseudorosette because the central structure isn’t

part of the tumor. Originally, pseudorosette meant any rosette that didn’t have a truly empty
lumen)
• True ependymal rosette - rosette with central lumen as tumor's attempt to make CSF
- Tumor can result in hydorcephalous

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