Pathophysiology: W1

What does a cell attempt to do before triggering apoptosis?

• A cell will try to adapt by repairing damages » to restore to normal function

What is the difference between a cell adaptation vs. injury?

• Adaptation is reversible » Atrophy, Hypertrophy, Hyperplasia

• Injury is irreversible and leads to cell dysfunction and potential death » Metaplasia and Dysplasia (a warning sign that injury will likely follow)

Define atrophy, hypertrophy, hyperplasia, metaplasia, and dysplasia.

• A decrease in cell size from disuse, denervation, loss of endocrine stimulation, inadequate nutrition, or ischemia

• An increase in cell size from increased workload, or compensation from the loss of an organ

• An increase in the number of cells, breast and uterine tissue during pregnancy experience this.

• Typically occurs during stress when better suited mature cells will come replace the ones currently in place(its specific to the primary tissue category: connective » connective)

• Dysplasia is when a cell becomes entire abnormal, typically a sign of cancer.

What 6 categories actually cause cellular damage? Explain.

• Hypoxia(#1) ischemia, lack of O2

• Chemical/Drug: Medication toxicity, poison, alcohol, environment

• Infectious/ Immunologic: ‘self v self’, pathogens

• Nutritional Imbalance: Deficiency in critical proteins or even excess, obesity

• Physical/Mechanical: Trauma, excessive heat/cold, radiation, pressure

• Genetic Derangement: Inborn errors » disrupt normal cell function

What are the steps toward ‘the point of no return’? Explain.

• Normal cell » Stress/Injury » Removal of the stress/Injury(surgery) » The damage has overwhelmed the cell » Cell death (necrosis or apoptosis)

If a tissue has bene without O2 for a significant period of time and all of a sudden receives O2, what could the possible outcomes be?

• The tissue could recover entirely, if the ischemia isn’t too severe

• Reperfusion injury: additionally injury after the O2 returns

• Cell death: ischemia lasted too long

Explain the Hypoxic injury.

Not enough O2 is reaching the cell.

• NO O₂ → NO ATP → PUMP FAILS → CELL SWELLS → LACTIC ACID ↑ , PH ↓→ DAMAGE TO MEMBRANE → DEATH

• If the cell ruptures and leaks it has the potential to damage cells around

Explain the reperfusion paradox.

The return of O2 is good, but if ischemia occurred for too long how does this damage the cell.

• Sudden return of 02 » Surge of free radicals (ROS) » Calcium overload & membrane damage » DAMP release & inflammation » Cell death (Apoptosis/Necrosis)

What are the 2 ways a cell dies? Explain.

• Necrosis: Unplanned (triggered by injury), swells + ruptures(spills) » triggers inflammation affecting surrounding cells

vs.

• Apoptosis: Planned, cell shrinks » stays packaged and eaten

Why does the way a cell die matter in the presence of neoplasia?

• Cancerous cells typically want to disable apoptosis so that growth can be rapid.

• A normal cell thats damaged/acting strange is scheduled to die rather than continue multiplying

Explain the 2 trigger pathways of apoptosis.

Intrinsic: DNA damage, stress, lack of growth signals

• Mitochondria release cytochrome c » activation executioner caspases

Extrinsic:

• A death signal binds to a death receptor on the membrane » activating the initiator » then the executioner

KEY: Both pathways end in the CASPASE ACTIVATION » this shared pathway leads to no spillage of cellular contents

What are the different types of necrosis?

• Coagulative: firm » blood supply cut off firms the heart

• Liquefactive: pus » brain infarction from death tissue that turns to liquid

• Caseous: cheese » TB in the lungs

• Fat necrosis: fat destroyed » Pancreatitis

• Gangrenous: dead limb or tissue, wet or dry tissue » severe ischemia in the limb or diabetic foot

Why do cells store the wrong thing?

• Cellular stress/injury → metabolism/transport is disrupted → substances build up → cellular accumulation

What are some substances cells store in the moments of stress?

Steatosis » Lipid accumulation » typical in liver cells

Protein Accumulation » in the kidneys too much protein from damaged filter» the filtrate is overwhelmed and some of the protein leaks into urine.

Pigments » excess bilirubin » leads to jaundice

• Other pigments melanin or hemosiderin

Dystrophic calcification (chronic) » Ca+ deposits in dead/damaged tissue » hard and stiff

Metastatic calcification(acute) » Ca+ is deposited in blood » increasingly over time hardens the tissue

What are the dangers of free radicals, and how does our body counter them?

The unstable electron steals from nearby structures » damaging membranes, proteins, and DNA.

• comes from = radiation, reperfusion, chemical toxins, normal metabolism » damages the lipid membranes, proteins, and DNA strands

• can potentially lead to cancer

Antioxidants = vitamins like A, C, E neutralize these radicals, and enzymes do as well

• it supports wound healing and aging by reducing ROS damage and helping protect cells and tissue so they can repair and function properly

What if a cell is exposed to a mild stressor but the stress is removed before permanent damage occurs? What happens?

The cell can undergo reversible injury and return to normal once the stressor is removed.

What if a cell's mitochondria suddenly stop producing ATP? Why would the cell start malfunctioning?

ATP is needed for many cellular processes, including the Na⁺/K⁺ pump, so the cell can't maintain homeostasis and begins to swell.

• also, PH would decrease cause of the use of glycolysis.

What if a cell suddenly produces way more free radicals than its antioxidants can neutralize?

Oxidative stress occurs, causing damage to DNA, proteins, and cell membranes.

What if free radicals damage a gene that normally tells a cell when to stop dividing?

The mutation could contribute to uncontrolled cell growth and potentially cancer.

What if a blood clot blocks a coronary artery and the heart tissue dies? What type of necrosis would you expect?

Coagulative necrosis.

What if caspases suddenly become activated inside a cell? What are they going to do?

They activate the apoptotic cell-death pathway, ultimately dismantling the cell.

What if a damaged heart valve becomes progressively stiff because calcium deposits build up on it? Which type of calcification?

Dystrophic calcification because the tissue was already damaged.

A patient has ischemia followed by PCI. What two seemingly opposite things are happening to the cells?

Ischemia causes oxygen deprivation and cellular injury, while PCI restores oxygen through reperfusion, which can paradoxically cause additional ROS-related injury.

A brain cell dies because of lack of oxygen. What happened first, and what happens to the tissue afterward?

Ischemia → cellular death → enzymatic digestion → liquefactive necrosis.

What happens when a cells instruction manual is altered?

The result is a genetic or congenital disorder

What are the 3 terms many commonly mix up?

• Congenital » present at birth, ex: fetal alcohol syndrome

• Hereditary » passed from parent to offspring, ex: Huntington syndrome

• Genetic » caused by a gene or chromosome abnormality, ex: new trisomy 21 in a child with unaffected parents

What are the 3 categories of genetic disorders? Explain.

Chromosomal » extra, missing or rearranged chromosome, ex: Down Syndrome(+1 copy of chromosome 21), Turner syndrome(missing X)

Single-gene » when a gene is mutated » abnormal gene protein/function(can be predictable), ex: Sickle cell disease

Multifactorial » multiple factors contribute to disorder, ex: genetic susceptibility + environmental factors

What are some important vocabulary terms behind inheritance patterns?

• Allele » specific versions(eye color ex.): brown allele, blue allele, green allele. You inherit one allele from each parent

• Homozygous » You inherited two identical alleles

• Heterozygous » You inherited two different alleles

• Genotype » actual genetic combination of alleles

• Phenotype » physical appearance, observable trait

• Dominant » allele that masks or hides the presence of another allele.

• Recessive » allele that gets hidden by a dominant allele

• Codominance: If a red flower allele and a white flower allele show codominance, the offspring doesn't turn pink (that would be incomplete dominance); it grows a flower with both red spots and white spots.

How does chromosomal error occur? Explain.

Nondisjunction: WRONG NUMBER

• a chromosome doesn’t separate correctly during meiosis » leading to -/+ of a chromosome, ex: trisomy 21 or Turners

Translocation: WRONG ARRANGEMENT

• A chromosome breaks off and moves to another chromosome perfectly

• Balanced v. Unbalanced: you could be unaffected by this » your offspring is more likely to be affected(inherited down syndrome)

What are the other ways a chromosome breaks off — besides translocation? Explain.

• Deletion » broken portion is lost, with all genes within

• Inversion » a piece of the chromosome breaks off, flips around, and attaches back backward

• Ring formation » beginning and end of a chromosome straight line turn into a ring

• Isochromosome » when 1 arm is lost and the other duplicated twice

What can cause the initial chromosome breakage?

• radiation exposure, certain chemicals, extreme cellular stress, or viral infection

What are the 5 chromosomal syndromes?

• Down syndrome, 3 copies instead of 2 » intellectual challenges, characteristic facial features, congenital heart defects

• Turner syndrome, missing X » short stature, webbed neck, infertility (some don’t realize they have Turners until puberty)

• Klinefelter syndrome, extra X » common in males, tall stature, small testes, infertility, develop secondary female sex charac.

• Trisomy-18 (Edwards) » 3 copies of 18, intellectual challenges, low birth weight, low survival during infancy

• Trisomy-13 (Patau) » 3 copies of 13, sever midline defects, cleft lip, low survival during infancy

What is the best way to predict patters of inheritance before genetic testing?

• a pedigree, or a family tree

What are the 3 main patterns of inheritance for single-gene disorders, and what is the risk for each?

• Autosomal dominant » 50% if one parent is affected, ex: Huntington disease

• Autosomal recessive » 25% if both parents are carriers, ex: Cystic Fibrosis, Tay Sachs, PKU

• X-Linked Recessive » Sons of carrier mothers are at highest risk, ex: Hemophilia A and Duchenne MD

What is the single gene disorder that can be seen across 3 systems? What are the systems? Explain.

Marfan’s Syndrome(AD): the FBN1 gene which will directly affect the fibrilin 1 protein » this protein directly give connective tissue its structure

1. Skeletal » tall stature, long limbs, flexibility from loose joints

2. Ocular » the lens dislocates from weakness

3. Cardiovascular » the aortic wall weakens which leads to its eventual rupture = DEATH

** cardio » the main cause of premature death in marfan’s syndrome

As a nurse, if you get a patient with Marfan’s syndrome, what is your priority?

• regular cardiovascular monitoring

• limit activities that would strain on the already weak aorta

What is Neurofibromatosis, and its 2 types? Explain

Causes tumors along the nerves and other tissues

• NF-1 (more common)» tumor suppressor gene on chromosome17 » soft skin tumors, learning disabilities, small % get malignant tumor transformation

• NF-2 » tumor suppressor gene on chromosome 22 » tumors on the acoustic nerve = hearing loss, tinnitus

What leads to autosomal recessive metabolic disorders?

• Missing necessary enzymes leads to toxins building up

• This is why new born testing is critical

What are autosomal recessive metabolic disorders?

PKU:

• enzyme meant to process phenylalanine is missing » builds to a toxic level » causing severe irreversible intellectual disability

• can be placed on a phenylalanine-restricted diet

Tay Sachs:

• missing enzyme that processes lipids in neurons » accumulation » infants seem normal that rapidly develop loss of motor skills, weakness, seizures, and blindness at around 6 months

• no treatment

What is the most common inherited intellectual disability?

Fragile X Syndrome:

• X -linked disorder

• The FMR1 gene on the X chromosome abnormally keeps repeating eventually becoming too long » its protein eventually stops being produced(necessary for brain development) » symptoms of long face, intellectual disability, large ears, start to show

What is unique about the mitochondrial inheritance pattern?

1. Mitochondria have their own DNA

2. Mitochondrial DNA comes only from your mother

3. It affects high-energy organs » Brain, muscle, eyes

Clinical presentations: muscle weakness syndromes, seizures with stroke-like episode, progressive vision loss

Explain multifactorial disorders. What is the #1 example?

The balloon analogy + threshold concept:

Genes → add some risk

• more affected relatives increases your risk

Environment (teratogens)→ adds some risk

• Alcohol, medications, maternal infections, radiation

if the balloon pops » Threshold has been crossed and the disorder will appear

Ex:

• Cleft palate

• Folic Acid » Neural tube Defects(Spina Bifida & Anencephaly) = the modifiable risk factor is folic acid intake

Explain the process of CRISPR-Cas9. What disorder

A guide RNA finds the target DNA, Cas9 cuts it, and the cell's repair process makes the desired change

What are some screening tools test for risk?

• Cell-free DNA/NIPT » as early as 10 weeks

• First-trimester screen » 11-14 weeks

• Quad screen » 15-20 weeks

• Newborn heel-stick » 24-48 hours after birth

What are some diagnostic tool?

• CVS(Chorionic Villus Sampling) » 10-13 weeks

• Amniocentesis » 15+ weeks

What is the role of a nurse when explaining a positive screening?

• positive screen is not a diagnosis, its simply an indicator that further diagnostic testing and counseling will be needed.

What is the nurses role when dealing with families that may have genetic risks?

• Pedigree » look at the family history

• Prenatal and newborn screening » explaining the purpose, timing, and result of the screening

• Psychosocial support » support the family through any guilt, grief, or even decision-making processes

• Refer to a genetic counselor » a counselor can accurately interpret screening results, know when it is time to refer

Define neoplasia.

abnormal, untrolled cellular growth

What 2 cancer’s are actually malignant despite their name?

Neuroblastoma and Melanoma

What are risk factors a person is able to avoid?

• Tobacco use

• Excess alcohol intake

• Obesity + Sedentary lifestyle

• UV exposure

• Certain infections you can get vaccinated for(HPV, Hep. B/C)

What are risk factors a person is not able to avoid?

• Age

• Inheritied mutaitons

• Family history

• Some chronic conditions » ulcerative colitis

What are key characteristics of a benign tumor?

• Slow growth

• Well-defined borders

• Cells look how they originally did

• Stays in the same area, does not metastasize

• Does not reoccur after its removed

What are the key characteristics of a malignant tumor?

• rapid, uncontrolled growth

• irregular, infiltrating borders

• calls look abnormal and are not differentiated

• it will invade nearby tissue

• can metastasize

• it is common for it to come back if a incomplete removal

T/F » Benign tumors are considered harmless in all cases.

FALSE

• benign tumors, depending on location(brain), can be deadly because of removal

What is carcinogenesis and its process?

how normal cells gradually become cancer » from a carcinogen: anything that can contribute to causing cancer

1. Initiation » the carcinogen causes irreversible DNA damage

2. Promotion » repeated exposure to the carcinogen » proliferation of impacted cell

3. Progression » increase in abnormality through mutations

What are common initiators and promoters of cancer?

• Chemical » Tobacco smoke, asbestos, industrial chemicals, food preservatives

• Radiation » UV light on skin, ionizing radiation

• Viral/Biologic » HPV » cervical cancer, Hep. B/C » liver cancer, H. pylori » stomach cancer

• Hormonal » long term estrogen exposure is linked to breast and endometrial cancer

What are the 2 genes cancer loves to exploit?

Oncogenes : the gas pedal thats stuck

• genes that help cells grow is now stuck going and can’t stop

Tumor suppressor genes : the cut off breaks in a car

• STOP gene indicating to the cell to stop growing is gone

• p53 & BCRA1+2 are tumor suppressor genes

What are the different ways oncogenes get turned on?

Gene amplification:

• too many copies of HER2 » excess growth = breast cancers forming

Translocation:

• Chromosomes 9 & 22 swap » BCR-ABL forms » causes nonstop cell growth = CML cancer forms

• MYC moves to antibody gene » MYC is over produced » too much growth = Burkitt Lymphoma cancer forms

Explain the Two-Hit Hypothesis.

If you have 2 copies of a suppressor gene with 2 scenarios:

• Inherited: Born with 1 hit → 1 more hit → tumor

• Sporadic: Normal → hit 1 → hit 2 → tumor

Sporadic is much more unlikely and will likely show itself over a lifetime.

EX: Retinoblastoma

What happens if tumor suppressor gene is the ‘first hit’? What if its the ‘second hit’ as well? Explain.

You can inherit a broken tumor-suppressor gene » this is classified as the first hit (even missing one tumor suppressor gene you are almost 100% likely to get cancer)

• BRCA » DNA repair is broken = mutation buildup » increases the risk for many cancers

Tumor suppressor genes can mutate and turn cancerous, the second hit.

• FAP is caused by a mutation in the APC tumor-suppressor gene

• APC mutation → hundreds of colon polyps → some can become cancerous

What are the 8 ways a cell turns cancerous?

• Ignores signals to stop cell growth

• Escapes apoptosis

• Achieves unlimited replication

• Triggers angiogenesis » growing its own blood supply

• Invades nearby tissue

• Metastasizes to nearby tissue

• Genome instability » cancer cells accumulate DNA mutations » DNA just get more and more messed up

• Evading immune destruction is something cancer cells are really good at » they hide in plain sight

Why can’t cancer die of old age?

• The telomerase that tells the cell to stop dividing is kept by cancer cells

• Cancer loses contact inhibition, so even when they come in contact with other cells they will continue to grow.

• Te loss of anchorage dependence allows cancer cells to survive and multiple without being attached to surrounding structures

What is the immune systems cancer surveillance team?

• Cytotoxic T cells » abnormal cells displaying tumor antigens, kill those

• Natural Killer Cells » attacks any abnormal cell quickly

• B Cells & Antibodies » Tags the cancer cell

• Macrophage » Alert + Help destroy

This is the basis for immunotherapy, to disable the breaks cancer cells put on the immune system

How does a cancer cell become invasive?

1. Normal epithelium

2. Dysplasia » crucial moment to catch the abnormal cell growth

3. Carcinoma in situ » controlled, can be surgically be removed

4. Invasive carcinoma » this requires aggressive treatment and even surgical removal

This is why screening is SOO IMPORTANT » catch the disease before it becomes invasive and spread

Why is early detection so important with cancer?

Doubling time » Cancer can grow for a long time while it's too small to detect. Once it gets larger, growth can become much more noticeable.

• EX: if a tumor has 1 million cells and its doubling time is 1 month:

  1 million → 2 million → 4 million → 8 million...

• SCREENING IS SO IMPORTANT » if you wait for symptoms it could be too late

What are the local effects of tumors?

Compression:

• tumors push/press of nearby structures » brain tumors are dangerous for this reason

Obstruction:

• tumors can block and opening » block the bowel leads to obstruction

Tissue destruction:

• invasive tumor will damage and destroy any structure around it

Bleeding/Ulceration:

• tumors could have fragile blood vessels or damage to the surface of tissue which can cause bleeding

What problems to cancer cause throughout the entire body?

Cancer cachexia»

• sever weight loss, muscle wasting, and weakness from the high caloric demands from cancer.

Paraneoplastic syndromes»

• the tumor releases substances(hormones) that cause symptoms somewhere else in the body

Can fluids build up in empty spaces while you have cancer?

Yes, this can happen with tumors that are near the surface of the skin, where the cancer will block lymphatic drainage systems.

• Pleural effusion → around the lungs

• Peritoneal effusion (ascites) → abdomen

An unexplained effusion can be an important clue to cancer » further investigation

What are the other underlying effects of cachexia?

Fatigue:

• Cancer fatigue = extreme/persistent tiredness that isn't simply fixed by sleeping

Anemia:

• Anemia = not enough healthy red blood cells to carry oxygen effectively

Cancer → several possible causes → anemia → less oxygen delivery → fatigue can occur

Explain the journey of metastsis.

D » detachment

L » local invasion

I » invades circulation system

S » survive circulatory system from immune cells

E » exit circulation system

C » colonize

What are the different ways the original tumor travels to another part of the body?

1. Hematogenous(through the blood)

• enter the bloodstream and travel to another organ

• colon cancer » liver

2. Lymphatic = through the lymph

• Cancer cells travel through lymph vessels

• Breast cancer → axillary lymph nodes

2. Seeding

• Cancer cells like to enter the bodies cavities

• Ovarian cancer → peritoneal cavity

What is grading v. staging?

Staging:

• “How far has it spread?”

• T = Tumor size/local invasion

• N = nearby lymph Nodes

• M = distant Metastasis

Grading:

• “How abnormal does it look?”

• Grades 1 » 4 (differentiated to not a all differentiated)

Does an elevated amount of tumor markers confirm a person has cancer?

• A marker can be high even when someone doesn't have cancer.

• A person can have cancer while the marker is normal.

What are the common tumor markers and what cancers are they associated with?

• PSA → Prostate

• CA-125 → Ovarian

• CEA → Colorectal

• AFP → Liver & testicular

• CA 15-3 / CA 27-29 → Breast

How do we confirm a diagnosis?

• Biopsy

• Imaging

• Lab studies

• Cytology

What are the 5 main ways cancer can be treated and the end goal?

• Surgery = Remove

• Chemo = Kill dividing cells

• Radiation = Damage DNA

• Targeted = Hit specific cancer feature

• Immunotherapy = Help immune system attack

What are the common side affects with cancer treatments?

Chemo → bone marrow, mouth/GI problems, hair loss
Radiation → skin + fatigue
Immunotherapy → immune/autoimmune reactions

What does the CAUTION mnemonic entail?

CAUTION = cancer warning signs

• C — Change in bowel or bladder habits

• A — A sore that does not heal

• U — Unusual bleeding or discharge

• T — Thickening or a lump in tissue

• I — Indigestion or difficulty swallowing

• O — Obvious change in a wart or mole

• N — Nagging cough or hoarseness

Why are childhood cancers different from adult cancer?

Childhood cancers are different from adult cancers. They more often affect the blood, nervous system, connective tissue, and kidneys. Some are embryonal tumors that develop from immature tissues.

What are the important late effects of childhood cancer treatment?

Even after the cancer is cured, treatment can cause health problems years later, so a history of childhood cancer remains important throughout life.

• Alkylating chemo → fertility problems + possible second cancer

• Anthracyclines → heart damage

• Radiation → growth/musculoskeletal problems + skin cancer risk

• CNS treatment(leukemia) → possible long-term cognitive problems

Why is it so significant to ask a for a patients health history, especially if they are expressing cancer symptoms?

• A patient's health history can reveal past cancers, risk factors, family history, previous treatments, and other conditions that may help explain their symptoms and identify their cancer risk.

• Childhood cancer that was healed may come back later in life