Gen Path Exam 1

Homeostasis

The tendency to maintain internal stability, health

Pathology

Disruption in homeostasis

\
Study of disease - Changes in cells, tissues, organs, altered biochemistry, structure & function.

Nature Vs Nurture

Nature →

Genetics, physical appearance, biological influences

\
Nurture →

Environmental, upbringing, social influences

Etiology

Origin of disease, the “why”

\- Genetics

\- Environmental exposures

\- Risk factors

Pathogenesis

Steps in development, the “how”

\
How those cellular changes occur

Know this chart

Hypertrophy

Increase in size

\
Incapable of division - overloading, increased GFs

\
Physiologic = weight lifting, pregnant uterus

\
Pathologic = ventricular hypertrophy

Hyperplasia

Increase in number of cells

\- Compensatory factors and gene activation

\- Hormonal factors

\
Physiologic = Liver donation, breasts and uterus

\
Pathologic = Human papillomavirus (HPV) - wart

\
Controlled

Atrophy

Decrease in cell size

\- Decrease protein synthesis

\- Increase protein breakdown

\
Reduced size and function

\
Causes:

\- Disuse

\- Denervation

\- Ischemia

\- Endocrine disruption

\- Aging (senile atrophy)

\
Cerebral Atrophy → risk for intracranial hemorrhage

Atherosclerosis, malnutrition, Alzheimer’s dx, Huntington’s dx

Metaplasia

Change of one cell type into another

\- More resilient

\- Reversible

\
Prologued stressors

\- Smoking

\- GERD

\
Consequences

\- Decrease in function

\- Malignant transformation

A wart is an example of which cellular adaptation?

Hyperplasia

Which cellular adaptation is most likely to represent a pre-cancerious change?

Metaplasia

Cell Injury & Death

When:

\- Stressor exceeds ability to adapt

\- Damage is directly induced

\- Intrinsic abnormality (inherited, genetic)

\
Trauma (physical, thermal, radiation), ischemia, hypoxia, poisons, infections, immune reactions, malnutrition, aging.

\
Types of cell injury:

\- Reversible

\- Irreversible

\
Examples of stressors that cause cellular injury and death:

Ischemia

Hypoxia

Toxins: glucose, poison, tobacco smoke

Infections

Immune reactions

Poor nutrition

Trauma

Aging

Reversible Injury

Transient or mild stressor

\- Minimal membrane damage

\- Nucleus is intact

\
Cellular swelling

Fatty accumulation (steatosis)

*Both of those are hallmark findings of an injured cell*

Irreversible Injury

*Death*

\
Prolonged or severe stressor

\- Irreparable mitochondrial damage

\- Damaged cellular membranes

\
Necrosis

\- Trauma, toxins, ischemia

\- Inflammatory

\
Apoptosis

\- Decreased growth factor or damage to DNA/proteins

\- Non-inflammatory

What leads to what chart

*See Image*

Nuclear Changes of Necrosis

Pyknosis - Solid, shrunken mass

\
Karyorrhexis - Fragmentation

\
Karyolysis - Fading, dissolution

Necrosis Vs Apoptosis

*See Image*

Necrosis

Death of living tissue

→ Loss of membrane integrity

→ Inflammatory

\
Patterns:

\- Coagulative (default)

*Gangrenous*

\- Liquefactive

\- Caseous

\- Fat (Enzymatic)

\- Fibrinoid

Coagulative Necrosis

aka ischemic necrosis

Severe ischemia, death of solid organ tissue

\- Infarction → Infarct (lesion)

\
Structure preserved

\- Firm

\- Days/weeks

\
ex. myocardial infarction

Gangrenous Necrosis

Gangrene = coagulative necrosis in an extremity

\- Peripheral vascular disease

\- Frost bite

\
Dry gangrene, wet gangrene, gas gangrene

Which pathology is most likely to cause gangrene in the US?

Diabetes

Liquefactive Necrosis

Dead cells are completely digested

\
WBCs digest tissues → liquid/viscous mass

\- CNS ischemia/hypoxia

\- Infections (wet gangrene)

*bacterial (MC - pus/abscess) or fungal*

Caseous Necrosis

“Cheese like”

Yellow, white, and friable

\
Tuberculosis (TB)

*M. Tuberculosis*

Chronic inflammation

“Caseous granuloma”

\
Granuloma = walled off collection of macrophages

Fat Necrosis

aka Enzymatic Necrosis

Fat destruction, fat “saponification”

\- Pancreatic lipases

\
Acute pancreatitis

\- Gallstones

\- Alcoholism

\
Pancreatic trauma

Trauma to breast

Fibrinoid Necrosis

Autoimmune Reactions

\- Immune complexes + fibrin

\-- arterial walls

\-- aneurysm risk

\
Histological Evaluation

\- Light microscopy

\
ex. Systemic Lupus Erythematosus

Polyarteritis Nodosa

Which of the following does NOT involve tissue death?

Atrophy

An HPV infection is most likely to cause what at the area of an epithelial infection?

Hyperplasia

Reduced blood flow to an organ or tissue is best described as what?

Ischemia

Inflammation is most likely to be associated with which form of irreversible cellular injury?

Necrosis

What pattern of necrosis is most likely to occur following severe ischemia?

Coagulative necrosis

A cardiac myocyte that is exposed to prolonged hypertension is most likely to adapt via what?

Hypertrophy

\
*9/10 this will be pathological, exception would be in runners/elete athletes*

Apoptosis

Programmed/Regulated

→ Unneeded or irreparable cells

→ Enzymatic breakdown, apoptotic bodies

\
Physiologic

→ Embryogenesis, endometrium, breasts, old WBCs

→ Autoreactive cells

\
Pathologic

→ Mutated cells, radiation exposure

→ Viral infections (T cells, HIV)

→ May accompany atrophy

Apoptosis Mechanisms

Activation of caspases = apoptosis

\
Mitochondrial (Intrinsic) Pathway

\- Decrease Growth Factor (GF), decrease DNA damage, decrease misfolded proteins

\- Increases mitochondrial permeability

\- Activates Caspase-9

\
Death Receptor (extrinsic) Pathway

\- Death Receptors bind with signaling molecules

\- Eliminates self-reactive lymphocytes or virally infected cells

\- Activates Caspase-8

Autophagy

“Self-Eating”

Lysosomal digestion of a cell’s insides

\- Organelles are sequestered/digested

\- Autophagic vacuoles

\
Survival during lean times

\- Prolonged leads to apoptosis

\
Rids misfolded proteins

\- Defects may contribute to pathology

\-- increase B-amyloid proteins = Alzheimer’s Dx

Mechanisms of Cell Injury

Mechanisms of Cell Injury *See Image*

Overview of Cellular Injury

Frequently begins with reduced ATP

\- ATP dependent pumps don’t work

*Ions accumulate within cell*

\- Cell death may follow.

\
Vulnerable cellular structures:

\- Mitochondria

\- Membranes

\- DNA

Cellular Injury

Ischemia/Hypoxic Injury

\- Acute cellular injury

\- Inhibits metabolism

\-- decrease O2 = decreased ATP and increased ROS

\- May be reversible, if blood/O2 supply is restored early

\
Persistent ischemia = Irreversible injury

\- Ruptures membranes → necrosis

\- Minimal apoptosis

Ischemia-Reperfusion Injury

Ischemia, followed by a restoration of blood

\- Increases inflammatory cells and increases ROS → Injury!

Reactive Oxygen Species

aka ROS aka Free Radicals

Molecules with an unpaired electron in their outer orbits

\
Redox reactions - partially reduced intermediate molecules

Inflammation/phagocytosis - bursts of ROS are created in by WBCs when digesting phagocytized material

Nitric Oxide is a natural free radical that is commonly produced by macrophages or endothelial cells

Ionizing radiation - hydrolyzes water into OH (Hydroxyl) and H (Hydrogen)

Ischemia-reperfusion injuries

Mitochondrial damage will cause what?

ATP to go down and ROS to go up

Pancreatitis is most likely to be associated with what?

Fat necrosis

What pattern of necrosis occurs following a cerebral infarction?

Liquifactive

Cellular Injury

Oxidative Stress → Accumulation of ROS

Cellular aging (redox), chemicals/toxins, irratiation

\
Inflammation (neutrophils/macrophages)

\
Ischemia-Reperfusion Injury

\

Cellular Injury

Chemical (toxic) Injury

Direct Injury : Toxins bind to cells

\- Cells that absorb, use, excrete, or store a toxin

\- Inhibit use of ATP or damages membranes

\
Latent Injury: Conversion into a highly reactive or toxic metabolites

\- Cytochrome P-450 (smooth ER of liver)

\- ROS → Membrane damage

\-- Acetaminophen

\-- N-acetyl-p-benzoquinone-imine (NAPQI)

Cellular Injury

Genetic Damage

Radiation, viruses, chemicals (chemotherapeutic meds)

\
Severe DNA damage

\
Triggers apoptosis

\
Mutations may contribute to carcinogenesis

Intracellular Accumulations

Abnormal Substances

\- Harmless or injurious

\- Cytoplasm, organelles, or nuclei

\- Injured or aged cells

\
4 Mechanisms:


1. Abnormal metabolism


1. Fatty liver disease


2. Defective protein folding or transport


1. Genetic mutations
3. Defective or absent enzymes
4. Ingestion of indigestible materials


1. Asbestos exposure

Fatty Change

aka Steatosis

Excessive lipid accumulation

\- Liver, heart, skeletal muscle, kidney

\
Macroscopic = hepatomegaly

Microscopic = fat vacuoles

\
Alcoholic Liver Disease

Non-alcoholic fatty liver disease

\- Type 2 DM, Obesity, dyslipidemia, malnutrition, HTN

Alcohol Metabolism

Ethanol (alcohol) is metabolized in the liver and a resulting large amount of NADH is produced

\
Increased NADH = increased lipid synthesis

Decreased lipoproteins to transport

Increased concentrations of lipids = lipid storage

Non-Alcoholic Fatty Liver

Metabolic Syndrome

\
Increased insulin resistance

\
Increased mobilization of fatty acids from adipose tissue

\
Hepatocytes will take up these free fatty acids

Heavy Drinking Effects

*See Image*

\
Know the percentages

Hepatocellular Carcinoma

aka Liver Cancer

Chronic Liver Disease

\- Chronic HBV infection

HCV Infections

Up to 20% of those with alcoholic cirrhosis will get this.

Aflatocin - mold (aspergillus flavus) - peanuts

Males are a 3 to 1 in this.

Pathologic Calcification

Dystrophic Calcification →

\- Calcification of damaged tissue

*Injury, aging, necrosis*

\- Normal Ca++ metabolism

Fibrodysplasia Ossificans Progressiva

Dysfunctional soft tissue repair

\- Autosomal dominant mutation

*Chromosome 4*

\
Rare

\- 1 per 2 million births

\
Trauma → heterotropic ossification

\- Ankylosis (fusion)

\- Severe deformation

\
Begins in infancy

Pathologic Calcification

Metastatic Calcification

\- Calcification of normal tissue

\- Abnormal Ca++ homeostasis

*Hypercalcemia (increased serum Ca++)*

Deposited into any tissues - vessels, kidneys, lungs, GIT

\
Types of Hypercalcemia:

Bone cancer, multiple myeloma, Paget disease, leukemia, hyperparathyroidism, hypervitaminosis D

Cellular Aging

Reduced functional capacity of cells

\- Accumulation of cellular/molecular damage

\

1. DNA damage - years of oxidative stress
2. Replicative senescence


1. Decreased mitosis
2. Shortened telomeres = arrest
3. Defective protein homeostasis


1. decreased synthesis and breakdown
2. Misfolding which leads to apoptosis

Progeroid Syndromes

Bloom Syndrome

→ Death in 20s

\
Werner Syndrome

→ Death in 40s

Inflammation Introduction

Homeostasis requires management of tissue damage

\
Inflammation →

\- Kills and eliminates microbes

\- Removed debris

\- Initiates repair

\
*Without inflammation, wounds would never heal!*

Inflammatory Cells and Inflammatory Mediators (Chemicals)

Immune Cells

\- Sentinel Cells

*already in tissue*

\- White blood cells: In circulation

*Must leave circulation and enter tissues to do job*

\
Inflammatory Mediators Chemicals

\- Released by immune cells

Sentinel Cells

Already located in tissues around the body

\
Macrophages → May have tissue specific name

Mast Cells

Dendritic Cells → May have tissue specific name

Leukocytes - In Circulation

Lymphocytes → T-cells, B-cells, Plasma cells, NK cells

*Create memories, very specialized approach of attack. Adaptive Immune System*

\
Monocytes → Macrophage

*Innate Immune System*

\
Neutrophils

*Innate Immune System*

\
Eosinophils

*Innate Immune System*

\
Basophils

*Innate Immune System*

Immune Cells Charts

*See images*

Inflammation

Response - Process


1. Identify stimulus/trigger
2. Kill and clean
3. Healing

\
\

Stimulus

Injury to normal vascular tissues

\
Can include:

Tissue damage

Injuries

Infections

Inappropriate immune response (allergies, auto immune)

Cardinal Signs of Inflammation

Rubor = Redness

Color = Heat

Tumor = Swelling

Dolor = Pain

Functio laesa = Loss of Function

5 Rs of Inflammation

Recognize injury/microbe

Recruit leukocytes

Remove agent (phagocytosis)

Regulate response

Resolution (repair)

Inflammation

Acute vs Chronic

Acute →

Rapid onset, minutes to hours

Short duration: several days

Cardinal signs of inflammation: local and systemic regions, no fibrosis

Neutrophils present

\
Chronic →

Insidious onset: multiple days

Longer duration: even lasting years

Few sings, angiogenesis, fibrosis

Macrophages, lymphocytes

Acute Inflammation

What are the stimuli?

\- Infection

\- Trauma

\- Ischemia

\- Necrosis

\- Foreign bodies

\- Hypersensitivity reactions (allergies and autoimmune)

\
How does the body recognize the stimulus?

\- Immune cell recognition of non-self

\- Immune cell recognition of damage

Recognition of Non-Self in Acute Inflammation

The first step in the inflammatory process is recognition of pathogens or damaged cells

\
Recognition of harmful (non-self) molecular patterns

\- Pamps

*pathogen associates molecular patterns*

ex. Toll-like receptors

located: plasma membrane, endosomes

Recognition of Damage in Acute Inflammation

DAMPS

*Damage associated molecular patterns*

Released from damaged or dying cells

\- Uric acid, ATP, decreased K+, DNA

\
This stimulates damaged cells to release IL-1

\- IL-1 induces inflammation & recruits inflammatory cells to the area

\- Major implication for: Inflammatory diseases

*Rheumatoid Arthritis, Lupus, etc*

Vascular Change in Acute Inflammation

The second step in the inflammatory process is vascular change

\
Inflammatory cells and chemicals are:

\- Recruited to an area of the body

\- Must exit vasculature and enter tissues

Vascular Changes

Alteres Caliber and Permeability

\- WBCs and Proteins → Target tissue

\

1. Vasoconstriction


1. Seconds - basically a non point, cause it happens so fast and then is done.
2. Vasodilation


1. Increased blood flow
2. Redness (erythema) and warmth
3. Increased vessel permeability


1. Edema → Target tissues
2. Increased blood viscosity → Stasis → WBCs collect along vascular wall (margination) → diapedesis

Mechanisms of Increased Permeability

Endothelial Contraction → Gaps in postcapillary venules

*Histamine*

\
Endothelial Necrosis → Leaky (until repaired)

*Burns, severe infections, irradiation*

\
Angiogenesis → New vessels have immature (leaky) endothelia

*Tissue repair, tumors*

Edema

Exudate → Protein rich edema

\
Transudate → Protein poor edema

Lymphatic Response

Lymphatics → Return excess fluid back to circulation. Does this by passing through lymph nodes as a screening/cleaning procedure to allow immune system to inspect along the way.

\
Lymphadenopathy - Disorder of lymph nodes (generic)

\
Lymphadenitis - Inflamed nodes, increase in size/pain

\
Lymphangitis - Inflamed lymphatic channel, red streak

\
*-ade- = node; -and- = channel/vessel*

Leukocyte Recruitment

Exiting Vasculature - Entering Inflammed Tissue

\
Steps:


1. Margination and rolling - hit breaks so products can slow down (selectins)
2. Firm adhesion (integrins)
3. Diapedesis - transmigration, extravasation, emigration
4. Chemotaxis - immune cells using concentration gradient to travel to correct location, migration.

\

Leukocyte Activation

Leukocytes must be activated

\- Bacterial lipopolysaccharides

\- Cytokines

\- Complement proteins

Neutrophil Influx

Most prevelant blood cell within acute inflammation

\
Neutrophils→

\- Killed within 48 hours (via apoptosis)

\- Replaced by macrophages and lymphocytes

\
Leukocyte Activation →

\- Stimulated by microbes, necrotic tissues, or foreign bodies

\
Phagocytosis


1. Opsonization
2. Engulfment & degradation (via oxidative burst)

*when they drop off, they contribute to puss, cause they’re just dead*

Opsonization

Target/label a cell for destruction

\
Opsonins = Antibodies (IgG) & complement proteins

\
Enhance macrophages binding & breakdown

\- “Marked for death”

\- Opsonization

\
*Like a shark after a swimmer*

Leukocyte-Induced Tissue Injury

Inadvertent damage to normal cells (secondary tissue injury)

\
Once activated, WBCs are indiscriminant

\- Damage via ROS and enzymes

\- Secrete cytokines

\
Persistent Infections

\- TB and certain viral infections ex. HIV, VZV

\
Ischemia-Reperfusion Injuries

\
Hypersensitivity Reactions

\- Allergies, autoimmune conditions

Clinical Features of Inflammation

Systemic Effects

\- Acute-phase reaction = lethargy, somnolence, malaise, tachycardia, increased BP, anorexia, anhidrosis


1. Fever = pyrogens → prostaglandin synthesis


1. Hypothalamus = increase temperature (rigors)
2. Elevates Plasma Proteins = cytokines stimulate


1. Increase in C-Reactive Protein (CRP) and fibrinogen
2. Increase in Erythrocyte Sedimentation Rate


1. aka ESR or “sed rate”

\
\

Inflammatory Mediators

Prostaglandins

\- Pain, fever (>100.4F, 38C)

\
Substance P

\- Neurotransmitter

\- Pain

When might back pain be from an infection?

Unrelieved with rest (lying down)

\
Fever, localized pain with spinal percussion

\- Recent infection (skin or urinary tract)

\- History of IV drug abuse

Systemic Effects of Inflammation

Lab Values →

Normal Leukocyte count = 4,500-10,000

\
Leukocytosis = increased leukocytes in blood

\- 15-30k/mL, increased immature cells = shift to the left.

\- Infection:

Bacterial = increased neutrophils

Viral = increased lymphocytes

Systemic Effects of Inflammation

Leukemoid Reactions = Extremely Leukocytosis

\- Leukocyte count is 40-100k/mL

\- Mimics leukemia

\- Chronic inflammation

*Clostridium Difficile, TB*

\
Leukopenia = decrease blood leukocyte count (

Patterns of Inflammation

6 Types →


1. Serous
2. Fibrinous
3. Purulent/Suppurative
4. Ulcerative
5. Pseudomembranous
6. Granulomatous

\
1-6 → Not chronic

7 → Chronic

Patterns of Inflammation →

Serous

Serum accumulates within or below the epidermis, watery effusion (“blister”)

\- Burns, viral infections, autoimmunity

Patterns of Inflammation →

Fibrinous

Severe injury = increased vessel permeability

\- Large molecules out of circulation

\- Fibrin-rich exudate

\- Severe fibrosis (adhesions)

\- Pericarditis or pleuritis

Patterns of Inflammation →

Suppurative

aka purulent: local infection with pus-forming organism (staph, aureas)

pus = neutrophils, necrotic cells, and edema

abscess = area of pus accumulation

Patterns of Inflammation →

Ulcerative

Superficial area of tissue necrosis

\- Peptic ulcers, aphthous ulcer (canker sore)

Patterns of Inflammation →

Pseudomembranous

Pseudomembranous

\- Corynebacterium diphtheriae

\- Clostridium difficile

Granulomatous Inflammation

Granuloma = Pattern of chronic inflammation

\- collection of macrophages

\- few scattered lymphocytes

\
Conditions that produce it… lots, know TB

Outcomes of Acute Inflammation

Resolution → Regeneration and repair

\- Minimal injury in cells that can replicate

\- Permeability normalizes, WBC apoptosis, lymph drainage; returns to normal

\
Chronic Inflammation

\- Severe injury or little capacity for replication

\- Failure to remove offending agent

\- Frequent scarring

\
Scarring (fibrosis)

\- Severe injury, tissues can’t replicate

\- Alters structure = decreased function

\

Chronic Inflammation

Prolonges Inflammation

\- Unresolved inflammatory reactions: persistent infection/injury (TB, silicosis) or hypersensitivity reactions

\
Features:


1. Mononuclear leukocytes


1. macrophages, lymphocytes, plasma cells
2. Tissue destruction
3. Angiogenesis and fibrosis

\
Lymphocytes = innate and adaptive immunity

\- B cells → plasma cells → antibodies

\- Sustain chronic inflammation: bacterial, viral, auto

\
Macrophages = dominant cell at areas of chronic inflammation

\- Phagocytosis of microbes and injured cells

\- Initiate angiogenesis and fibrosis: classically (M1) and alternatively (M2) activated.

Tissue Repair (Healing)

Restores structure and function

\
Beings before inflammation is eliminated

\
Mechanisms →

Regeneration: Replaces damaged cells to pre-injury status, stem cells proliferate, uninjured tissues

Scarring: Deposition of fibrotic tissue, severe structural damage, cell are unable to proliferate

Regeneration

Ability to replace injured tissues is variable


1. Cell’s inherent growth capacity (skin vs nerve)
2. Nature of injury (mild vs severe)


1. Extent of ECM damage
2. Damage to stem cells

\
Labile Cells - Skin, epithelia, constant division

Stable Cells - Capacity to repair, but aren’t constantly actively dividing

*hepatocytes are unique, regrow after 90% resection*

\

Fibrosis (Scarring)

Abnormal/extensive collagen deposition

\- Lungs, liver, kidney, myocardium

\- Frequently occurs following chronic inflammation and death of terminally differentiated cells

\- Myocardial infarction: infarct is a site that will result in fibrosis and be non contractile

Scar Formation (Fibrosis)

When tissues can’t regenerate

\
This can be due to:

\- Severe damage

\- Prolonged injury (hepatectomy vs liver cirrhosis)

\- Injury to terminally differentiated cells

\
Injured cells are replaced by connective tissue

\
In reality… It’s a combo of regeneration and fibrosis

\
Steps:


1. Angiogenesis
2. Fibroblast migration & proliferation
3. Collagen deposition → scar
4. Remodeling (lifetime)

\
Quickly…

Fibroblasts accumulate, endothelia begin diving

\
*Granulation Tissue*

Develops within 3-5 days, fibroblasts/WBCs, capillaries, connective tissue

Scar Tissue Deposition

Built upon granulation tissue


1. Macrophages secrete GFs that recruit fibroblasts


1. 3-5 days post injury
2. Fibroblast migrate/proliferate and irregular collagen (ECM) is deposited

\
Initially scars are vascular

Later scars become progressively avascular = pale scar (pallor)

Remodeling of Connective Tissue

Continually remodeled

\- Balance between ECM synthesis & breakdown

\
Matrix metalloproteinase (MMPs)

\- Breakdown collagen

\- Produced by: fibrobasts, macrophages, neutrophils, & epithelial cells

\- Zinc ions are a cofactor

\
Results of scarring are highly variable