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Advanced Pathophysiology: Cellular Adaptation, Injury, and Cancer Study Guide, Study Guides, Projects, Research of Nursing

This study guide provides an overview of advanced pathophysiology, focusing on cellular adaptation, injury, and death. It covers key concepts such as apoptosis versus necrosis, the role of sodium and calcium in hypoxic cell injury, and the effects of aerobic versus anaerobic metabolism. Additionally, it explores adaptation mechanisms like metaplasia and dysplasia, with specific examples such as bronchial metaplasia in smokers and barrett's esophagus. The guide includes questions and answers to reinforce understanding of these complex processes, along with an introduction to cancer, including cancer in situ (cis), proto-oncogene mutation, and the role of epigenetics and tumor-suppressor genes like p53. Finally, it touches on water and electrolyte balance, causes and mechanisms of edema, and redistribution shifts.

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Advanced Pathophysiology
Study Guide for Test #1
Unit-1
Cellular adaptation, injury, and death
- Apoptosis Vs necrosis
Apoptosis = Programmed cell death (suicide) Necrosis = Unregulated enzymatic digestion of cell
components
- Maintains a balance between cell proliferation and cell
death
– Functions to remove cells so new cells can replace them
– Highly selective process that eliminates injured and aged
cells
- Affects scattered, single cells
- Starts by shrinkage of the cell
- There is membrane-bound fragmentation of the cell
(CELL MEMBRANE STAYS INTACT). As a result,
intracellular enzymes are NOT released into
circulation
- Not associated with inflammatory reaction
- Interferes with cell replacement and tissue regeneration
- Non-distinguishing cell death
- Starts by swelling of the cell
- There is loss of cell membrane integrity >> Lysosomal
enzymes are released extracellularly (blood)
- Triggers inflammatory response in the surroundings
- Role of Na + and Ca ++ in hypoxic cell injury
Steps and mechanisms of cell injury
1. Hypoxia > reduced ATP production inside the cell
2. Failure of Na/K pump > more Sodium (Na) moves into the cell
3. High osmotic pressure > water moves into the cell > cell swelling
4. Dilation of endoplasmic reticulum and detachment of ribosomes > reduced protein synthesis
5. Increased lipid deposition, glycolysis, lactate formation, lowered pH, clumping of nuclear chromatin, increased
membrane permeability
>> Lecture:
Recall > Where sodium goes, water goes. Water will follow sodium and accumulate within the cell, resulting in cellular
edema. With sodium, the cell swells to a certain degree, and the cell membrane gives way/breaks (#6), allowing calcium
to get inside (#7).
When cells are hypoxic, they will accumulate lactic acid. The Na/K pump is a protein molecule and will denature
(breakdown) when exposed to lactic acid, to stop functioning altogether.
6. Loss of cell membrane integrity
7. Increased Calcium (Ca) influx > enzymatic activation > cell damage
8. Disruption of cytoskeleton
9. Mitochondrial membrane damage, lysosome swelling and rupture
10. Cell death (necrosis!)
>> Lecture:
Calcium is the “killer.” Calcium inside the cell is very restricted and is always kept outside the cell. The cell membrane
keeps calcium out; however, in the above scenario, calcium can come in. Calcium activates cellular enzymes and leads
to self-destruction (necrosis!).
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Advanced Pathophysiology Study Guide for Test # Unit- Cellular adaptation, injury, and death

- Apoptosis Vs necrosis Apoptosis = Programmed cell death (suicide) Necrosis = Unregulated enzymatic digestion of cell components

  • Maintains a balance between cell proliferation and cell death
  • Functions to remove cells so new cells can replace them
  • Highly selective process that eliminates injured and aged cells
  • Affects scattered, single cells
  • Starts by shrinkage of the cell
  • **There is membrane-bound fragmentation of the cell (CELL MEMBRANE STAYS INTACT). As a result, intracellular enzymes are NOT released into circulation
  • Not associated with inflammatory reaction**
  • Interferes with cell replacement and tissue regeneration
  • Non-distinguishing cell death
  • Starts by swelling of the cell
  • **There is loss of cell membrane integrity >> Lysosomal enzymes are released extracellularly (blood)
  • Triggers inflammatory response in the surroundings
  • Role of Na + and Ca ++ in hypoxic cell injury** Steps and mechanisms of cell injury
    1. Hypoxia > reduced ATP production inside the cell 2. Failure of Na/K pump > more Sodium (Na) moves into the cell
    2. High osmotic pressure > water moves into the cell > cell swelling
    3. Dilation of endoplasmic reticulum and detachment of ribosomes > reduced protein synthesis
    4. Increased lipid deposition, glycolysis, lactate formation, lowered pH, clumping of nuclear chromatin, increased membrane permeability >> Lecture: Recall > Where sodium goes, water goes. Water will follow sodium and accumulate within the cell, resulting in cellular edema. With sodium, the cell swells to a certain degree, and the cell membrane gives way/breaks (#6), allowing calcium to get inside (#7). When cells are hypoxic, they will accumulate lactic acid. The Na/K pump is a protein molecule and will denature (breakdown) when exposed to lactic acid, to stop functioning altogether. 6. Loss of cell membrane integrity
    5. Increased Calcium (Ca) influx > enzymatic activation > cell damage
    6. Disruption of cytoskeleton
    7. Mitochondrial membrane damage, lysosome swelling and rupture
    8. Cell death (necrosis!) >> Lecture: Calcium is the “killer.” Calcium inside the cell is very restricted and is always kept outside the cell. The cell membrane keeps calcium out; however, in the above scenario, calcium can come in. Calcium activates cellular enzymes and leads to self-destruction (necrosis!).

- Aerobic Vs anaerobic metabolism: effects in cell injury Anaerobic metabolism

  • Anaerobic metabolism occurs when little to no oxygen is available to the body (e.g., hypoxia, ischemia, infarct) **- 1 unit of glucose produces 2 units of ATP
  • Lactic acid is a byproduct which damages the cell**

Anaerobic metabolism occurs with hypoxia (e.g., ischemia or infarct). Decreased ATP production (only 2 units) due to lack of oxygen supply causes failure of the Na/K pump and Na-Ca exchanger, which leads to cellular swelling. Aerobic shutdown, or power failure, occurs >> converting to anaerobic metabolism. Na/K cannot work well. There is increased intracellular sodium (increased water as well because water follows sodium) contributing to cellular swelling. Cellular damage is caused by the increased lactic acid. More free radicals are produced >> more cell damage. Aerobic metabolism

  • Aerobic metabolism occurs when sufficient oxygen is available to the body (normal functioning!). **- 1 unit of glucose produces 32-36 units of ATP
  • No lactic acid w/ aerobic metabolism
  • Adaptation (Metaplasia)** Metaplasia: Reversible replacement of one cell by another cell type Bronchial metaplasia (in smokers!) - Normal columnar ciliated epithelial cells, are replaced by stratified squamous epithelial cells (no mucous secretion, no cilia) - Can be reversed (if the person stops smoking) - Can be transformed into cancer (if the person continues to smoke, metaplasia can continue to dysplasia) Barrett esophagus - Normal squamous epithelial lining of the esophagus, is replaced by columnar epithelium (goblet cells of the intestines) - Occurs as an adaptation to the chronic irritation of GERD - Predisposes to esophageal adenocarcinoma - Dysplasia Dysplasia: Atypical hyperplasia - Deranged cell growth of a specific tissue that results in cells that vary in size, shape, and organization - Epithelial tissue of the respiratory tract - Epithelial tissue of the uterine cervix - Precursor of cancer - Grading (low or high grade) (e.g., Pap smear) - Adaptive as it potential reversible Questions from PPT
  1. After ovulation, the uterine endometrial cells divide under the influence of estrogen; this is an example of hormonal: a. Hyperplasia b. Dysplasia c. Hypertrophy d. Anaplasia HORMONAL HYPERPLASIA Hormonal hyperplasia occurs chiefly in estrogen-dependent organs, such as the uterus and breasts. After ovulation, for example, estrogen stimulates the endometrium to grow and thicken for reception of the fertilized ovum.
  2. The abnormal proliferation of cells in response to excessive hormonal stimulation is called: a. Dysplasia b. Pathologic dysplasia c. Hyperplasia d. Pathologic hyperplasia PATHOLOGIC HYPERPLASIA Pathologic hyperplasia is the abnormal proliferation of normal cells and can occur as a response to excessive hormonal stimulation or the effects of growth factors on target cells.
  3. Removal of part of the liver leads to _______ of the remaining liver cells. a. Dysplasia b. Metaplasia c. Compensatory hyperplasia d. Compensatory dysplasia COMPENSATORY HYPERPLASIA Compensatory hyperplasia is an adaptive mechanism that enables certain organs to regenerate. For example, removal of part of the liver leads to hyperplasia of the remaining liver cells (hepatocytes) to compensate for the loss.
  4. During ischemia, what effect does the loss of the adenosine triphosphate (ATP) level have on cells? a. Cells shrink because of the influx of Ca b. Cells shrink because of the influx of KCl c. Cells well because of the influx of NaCl d. Cells swell because of the influx of NO C. CELLS SWELL BECAUSE OF THE INFLUX OF NACL A reduction in ATP levels causes the plasma membrane’s sodium-potassium pump and sodium-calcium exchange to fail, which leads to the intracellular accumulation of sodium and calcium and diffusion of potassium out of the cell. Sodium and water then can enter the cell freely, and cellular swelling results.
  5. What is a consequence of plasma membrane damage to the mitochondria? a. Enzymatic digestion halts DNA synthesis b. Influx of calcium ions halts ATP production c. Reduction in ATP production caused by edema from an influx in sodium d. Shift of potassium out of the mitochondria, which destroys the infrastructure B. INFLUX OF CALCIUM HALTS ATP PRODUCTION The most serious consequences of plasma membrane damage is hypoxic injury to the mitochondria. An influx of calcium ions from the extracellular compartments activates multiple enzyme systems resulting in cytoskeleton disruption, membrane damage, activation of inflammation, and eventually DNA degradation. Calcium ion accumulation in the mitochondria causes the mitochondria to swell, an occurrence that is associated with irreversible cellular injury. The injured mitochondria can no longer generate ATP, but they do continue to accumulate calcium ions.
  6. What is a consequence of leakage of lysosomal enzymes during chemical injury? a. Enzymatic digestion of the nucleus and nucleolus occurs, halting DNA synthesis b. Influx of potassium ions into the mitochondria occurs, halting the ATP production

c. Edema of the Golgi body occurs, preventing the transport of proteins out of the cell d. Shift of calcium out of the plasma membrane occurs, destroying the cytoskeleton A. ENZYMATIC DIGESTION OF THE NUCLEUS AND NUCLEOLUS OCCURS, HALTING DNA SYNTHESIS Enzymatic digestion of cellular organelles, including the nucleus and nucleolus, ensues, halting synthesis of DNA and ribonucleic acid (RNA).

  1. In hypoxic injury, why does sodium enter the cell and cause swelling? a. Because the cell membrane permeability increases for sodium during periods of hypoxia b. Because there is insufficient ATP to maintain the pump that keeps sodium out of the cell c. Because the lactic acid produced by the hypoxia binds with sodium within the cell d. Because sodium cannot be transported in the cytosol to the cell membrane during hypoxia B. BECAUSE THERE IS INSUFFICIENT ATP TO MAINTAIN THE PUMP THAT KEEP SODIUM OUT OF THE CELL In hypoxic injury, movement of fluid and ions into the cell is associated with acute failure of metabolism and loss of ATP production. Normally, the pump that transports ions out of the cell is maintained by the presence of APT and ATPase, the active-transport enzyme. In metabolic failure caused by hypoxia, reduced ATP and ATPase permit sodium to accumulate in the cell, whereas potassium diffuses outward.
  2. What organs are affected by coagulative necrosis that results from hypoxia caused by severe ischemia or caused by chemical injury? a. Lungs and pulmonary vessels b. Brain and spinal cord c. Kidneys and heart d. Muscles and bones C. KIDNEYS AND HEART Coagulative necrosis, which occurs primarily in the kidneys, heart, and adrenal glands, commonly results from hypoxia caused by severe ischemia or hypoxia caused by chemical injury, especially ingestion of mercuric chloride.
  3. What type of necrosis results from ischemia of neurons and glial cells? a. Coagulative necrosis b. Liquefactive necrosis c. Caseous necrosis d. Gangrene necrosis B. LIQUEFACTIVE NECROSIS Liquefactive necrosis commonly results from ischemic injury to neurons and glial cells in the brain.
  4. What type of necrosis is often associated with pulmonary tuberculosis? a. Bacteriologic necrosis b. Caseous necrosis c. Liquefactive necrosis d. Gangrenous necrosis B. CASEOUS NECROSIS Caseous necrosis, which commonly results from tuberculosis pulmonary infection, particularly tuberculosis, is a combination of coagulative and liquefactive necrosis.
  5. What type of necrosis is associated with wet gangrene? a. Coagulative necrosis b. Liquefactive necrosis c. Caseous necrosis

Cancer

- What’s CIS? CIS = Cancer in situ - Stage 0 - Pre-invasive epithelial malignant tumors, of glandular or squamous cell origin - Early stages of cancer, localized to the epithelium, have not broken through the basement membrane or **invaded the surrounding stroma

  • Proto-oncogene mutation
  • Role of epigenetics in cancer** Epigenetic silencing
  • Turns off genes without mutation
  • Silencing (e.g., by DNA methylation) can **shut off critical tumor suppressor genes
  • Role of P53 as a tumor-suppressor gene**
    1. Arrests the cell cycle - stops the cells from freely dividing aka cancer
    2. Activates DNA repair- fixes dna to make sure cells are normal, and that genes that prevent cancer still work
    3. Initiates apoptosis - “hey this cells, crazy and keeps dividing, kill it”
    4. Prevents angiogenesis - CA cells, need more blood to keep growing, normal cells DO NOT MAKE THEIR OWN BLOOD VESSELS, ONLY CANCER CELLS! angio=blood vessels genesis = growing new *Mutation of P53 inactivates these functions of P - Staging and grading of cancer Staging describes the extent or severity of a person’s cancer.
    • Five-stage scheme
    • TNM standardized staging Five-stage scheme Stage 0: Carcinoma in situ (Cancer that has not broken thru basal membrane) = has not metastasized yet Stage I: Cancer confined to the organ of origin Stage II: Cancer is locally invasive Stage III: Cancer has spread to regional structures (lymph nodes) Stage IV: Cancer has spread to distant sites TNM standardized staging
    • Primary tumor (T)
    • TX: Primary tumor cannot be evaluated
    • T0: No evidence of primary tumor
    • Tis: Carcinoma in situ
    • T1, T2, T3, T4: Size and/or extent of the primary tumor
    • Regional lymph nodes (N)
  • NX: Regional lymph nodes cannot be evaluated
  • N0: No regional lymph node involvement
  • N1, N2, N3: Degree of regional lymph node involvement
  • Distant metastasis (M)
  • MX: Distant metastasis cannot be evaluated
  • M0: No distant metastasis
  • M1: Distant metastasis is present Grading Low-grade: Well differentiated (this means the tumor cells are organized and look more like the normal tissue ). High grade: Poor differentiation (cancer cell is not organized and does not resemble the tissue it arose from ) - Telomeres
  • Telomeres are protective ends, or caps, on each chromosome, that get smaller and smaller with each cell division.
  • Short telomeres signal the cell to cease division
  • Cancer cells activate the enzyme telomerase* in order to restore and maintain their telomeres >> Allows for continuous division of cancer cells >> Cells do not cease dividing *Telomeres are placed and maintained by telomerase **Unit- Water & Electrolytes
  • Causes & mechanisms of edema
  1. Venous Obstruction:** increased capillary hydrostatic pressure. a) Ex: DVT pushes H2O out.
  2. Decrease Capillary Oncotic Pressure : hypoalbuminemia 3) Increase Capillary Membrane Permeability a) Ex: related to inflammation, burns, histamine release r/t anaphylactic shock **4) Lymphatic Obstruction
  • Different types and causes of Hyponatremia and hypernatremia Hyponatremia: Na < 135**
  1. Isotonic a. Pseudohyponatremia (lab error) b. Hypertriglyceridemia c. Hyperproteinemia
  2. Hypertonic a. Hyperglycemia (DKA or HHS) b. Mannitol
  3. Hypotonic (Treatment: Normal saline) a. Hypovolemic i. Both Na and water are lost, but with MORE Na loss ii. Dehydration iii. Non-renal (urine Na < 10 mEq)
  4. Vomiting/diarrhea

↑K

Clinical manifestations:

- Cardiac arrhythmias and muscle weakness

- EKG changes: Tall, peaked T-waves

Causes:

1. Impaired urinary excretion

a. Renal failure

b. Hypoaldosteronism

c. ACE inhibitors

d. ARBs

2. Internal redistribution “shifts”

a. Cell lysis

i. Tumor lysis syndrome

ii. Massive hemolysis

iii. Rhabdomyolysis

b. Medications

i. Beta-blockers

ii. Digoxin toxicity

c. Other

i. Insulin deficiency (DKA)

ii. Acidosis

iii. Exercise

iv. Hyperkalemic periodic

paralysis

↑Ca

Clinical manifestations:

- “Stones, bones, groans, and psychotic

overtones”

- Nephrolithiasis (kidney stones)

- Bone pain

- Abdominal pain

- Depression, anxiety, confusion

- Constipation, anorexia, nausea, weakness,

lethargy

- EKG findings: short QT interval

- Dehydration

- Renal insufficiency

- Nephrogenic diabetes insipidus

Causes:

1. PTH excess

a. Hyperparathyroidism

i. Adenoma

ii. Hyperplasia

iii. Carcinoma

b. PTHrP-secreting malignancy

2. Hormone-independent bone absorption

a. Osteolytic bone metastasis

b. Paget's disease of bone

c. Immobilization

3. Vitamin D excess

a. High intake of vitamin D

b. Ectopic vitamin D production

i. Sarcoidosis

ii. TB

4. Excessive dietary intake of Ca

a. Milk

b. Alkali syndrome

5. Thiazides (medication)

6. Rare miscellaneous cases

a. Adrenal crisis

b. Severe rhabdomyolysis

c. Theophylline toxicity

↓K

Clinical manifestations:

- Membrane hyperpolarization causes a decrease

in neuromuscular excitability

- Muscle weakness (legs > arms), cramps, ileus

- Cardiac conduction abnormalities (e.g., atrial

fibrillation, ventricular tachycardia)

↓Ca

Clinical manifestations:

- Tetany (repetitive discharge of peripheral

nerves after a single stimulus)

>> Symptoms of tetany: perioral paresthesias,

muscle stiffness, spasms and cramps, shortness

of breath (diaphragmatic spasms), diaphoresis

- EKG findings: ST depression, T-wave

inversion, prominent U-wave

Causes:

1. Reduced potassium intake

a. Starvation

b. Anorexia

2. GI loss

a. Vomiting

b. NG drainage

c. Diarrhea

d. Laxative abuse

e. Ureterosigmoidostomy

3. Urinary losses

a. Diuretics

b. Mineralocorticoid excess

c. Renal tubular acidosis

d. Amphotericin B

e. Polyuria

f. Hypomagnesemia

g. Salt wasting nephropathy

4. Redistribution “shifts”

a. Insulin

b. Catecholamines (b-agonists)

c. Alkalosis

d. Marked cell proliferation

(treatment of B12 deficiency

anemia)

e. Hypokalemic periodic paralysis

5. Increased potassium entry into cells

6. Increased potassium loss

7. Excessive mineralocorticoids

*Chvostek’s sign (facial spasm by tapping ear)

*Trousseau's sign (carpopedal spasm w/ BP cuff)

- Severe symptoms: Seizures, hypotension,

emotional lability, psychosis

- EKG findings: Long QT interval

Causes:

1. Hypoparathyroidism

a. S/p thyroidectomy

b. S/p therapy for Graves disease

c. Autoimmune hypoparathyroidism

d. Hypomagnesemia

e. Genetic or congenital

f. PTH resistance

2. Vitamin D deficiency

a. Low intake of vitamin D

b. Inadequate sunlight exposure

c. Malabsorption syndrome

d. Advanced CKD

e. Hyperphosphatemia

3. Low dietary intake of Ca

4. Miscellaneous causes

a. Osteoblastic bone metastasis

b. Pancreatitis

c. Multiple transfusions

d. Acute respiratory alkalosis

e. Hyperphosphatemia

f. Excessive use of bisphosphonates

(↓Ca): Tetany (e.g., Chvostek &

Trousseau signs)

Low calcium causes high excitability

STUDY TABLE THAT CAUSES HYPOKALEMIA/HYPERKALEMIA

Renal failure causes high potassium levels (you cannot pee it out through kidney excretion). High K is an indication for dialysis. Transcellular potassium shift Beta-agonist (albuterol) >> hypokalemia >> insulin infusion >> Alkalosis (sodium bicarbonate) Beta-blocker >> hyperkalemia >> DKA, HHS, Conditions of acidosis (too much hydrogen inside the blood vessels, in addition to potassium, where both are positively charged, some potassium is kicked out and hydrogen is taken in (an exchange). DURING ACIDOSIS, potassium moves out as a result.

**- Anion gap, delta gap, and evaluating multiple metabolic acid/base disorders

  • Causes of anion-gap and non-anion gap metabolic acidosis disorders
  • Causes of metabolic alkalosis, respiratory acidosis and respiratory alkalosis** Respiratory acidosis Respiratory alkalosis Metabolic alkalosis