Pathology: Etiology and Pathogenesis

Pathology

• Pathology studies structural, biochemical, and functional changes in cells, tissues, and organs underlying disease.
• It aims to explain the reasons behind a patient's signs and symptoms.
• Pathology provides the scientific basis for clinical care and therapy.
• Four key aspects of a disease are etiology, pathogenesis, morphologic changes, and clinical manifestations.

Etiology

• Etiology refers to the initiating cause of a disease.
• The two main categories of etiology are genetic and environmental.
• Genetic causes include mutations and gene variants.
• Environmental factors include infectious, nutritional, chemical, and physical causes.
• Multifactorial diseases involve a combination of genetic predisposition and environmental trigger.
• An example of a multifactorial disease is a smoker born with genetic risk for cancer having a higher chance of developing it.

Pathogenesis

• Pathogenesis is the sequence of molecular, biochemical, and cellular events that lead to disease development.
• It explains how underlying etiologies cause the morphologic and clinical signs of the disease.

Morphologic Changes

• Morphologic changes involve structural alterations in cells or tissues characteristic of a disease.
• They aid in diagnosing the etiologic process.

Clinical Manifestations

• Clinical manifestations are the signs and symptoms of a disease.

Cellular Response

• Normal cells can handle physiological demands and maintain a steady state of homeostasis.
• Adaptation refers to reversible functional and structural responses to changes in physiological states.
• Examples of adaptation include pregnancy and exposure to pathogenic stimuli.
• Cells achieve a new steady state to survive and function.
• After the stressor is removed, the cell can return to its original state.
• Exceeding adaptive limits, exposure to damaging insults, nutrient deprivation, or genetic mutations affecting cellular function leads to disturbed cell injury.

Causes of Cell Injury

• Oxygen deprivation can cause hypoxia or ischemia, such as in a stroke or heart attack.
• Physical agents include traumatic injuries or temperature extremes, like frostbite, burns, or electrical injuries.
• Chemical agents and drugs include toxins and certain medications.
• Infectious agents, like COVID-19, can cause cell injury.
• Immunologic agents can damage the body while fighting off infection.
• Genetic abnormalities can lead to cells more susceptible to damage.
• Nutritional imbalances can also make cells more susceptible to damage.
• Cell injury often has multiple causes acting in combination.

Cell Aging

• Cell aging involves a progressive decline in cellular function and viability.
• It results from accumulated cellular damage, reduced capacity to divide (replicative senescence), impaired DNA repair, and defective protein homeostasis.

Cell Death

• Cell death occurs when further progressive injury leads to a point of no return.
• It can also be an essential process in embryogenesis, organ development, and homeostasis.
• Cell death removes damaged, unneeded, and aged cells and is considered normal.
• Necrosis is enlarged (swelling) cell size, disrupted plasma membrane, enzymatic digestion and usually pathologic.
• Apoptosis is reduced (shrinkage) cell size, fragmentation into a nucleosome-size fragments, intact plasma membrane, release of apoptotic bodies and often physiologic.

Patterns of Tissue Necrosis

• Tissue necrosis occurs when a large group of cells die.

Coagulative Necrosis

• Coagulative necrosis preserves dead tissue architecture for a few days.
• It is caused by ischemia, due to a blood vessel obstruction, leading to an infarct.
• An infarct is a localized area of coagulative necrosis.
• The pattern is generally found in all organs except the brain.

Liquefactive Necrosis

• Liquefactive necrosis does not preserve dead tissue architecture.
• Digestion of dead cells transforms the tissue into a viscous liquid (pus).
• Necrotic material (pus) is frequently creamy yellow because of leukocytes.
• This pattern occurs in the brain and focal bacterial or fungal infections.
• Microbes stimulate leukocyte accumulation and enzyme liberation from these cells.

Gangrenous Necrosis

• Gangrenous necrosis refers to coagulative necrosis of the limbs, typically the lower extremities, due to lost blood supply.
• Generally considered coagulative necrosis involving multiple tissue planes.
• Wet gangrene involves superimposed bacterial infection leading to liquefactive necrosis due to degradative enzymes, bacteria, and attracted leukocytes.
• Wet gangrene is frequently seen in diabetic feet.
• Untreated wet gangrene can result in ascending infection and may require amputation.

Fibrinoid Necrosis

• Fibrinoid necrosis is observed in vascular damage from immune reactions.
• It occurs when antigen-antibody complexes deposit in artery walls causing plasma proteins to leak out of the vessel
• The result is an amorphous, bright pink deposit.

Caseous Necrosis

• Caseous necrosis is associated with tuberculous infection.
• It presents as a cheese-like, friable white appearance.

Fat Necrosis

• Fat necrosis involves focal fat destruction resulting from activated pancreatic lipases/enzymes entering the peritonal cavity.
• Grossly visible chalky white areas (fat saponification) result from fatty acid and calcium combination.

Tissue Repair

• Tissue repair, also known as healing, involves restoring tissue architecture and function after injury.
• This process is critical for survival.
• The inflammatory response eliminates dangers and initiates repair.
• Tissue repair occurs through regeneration or scarring.

Regeneration

• Regeneration restores normal cells.
• It occurs after mild injuries that damage the epithelium but not the underlying tissue and resolution occurs.

Scarring

• Scarring consists of connective tissue deposition.
• It occurs due to more severe injury with damage to the connective tissue and repaired by scar formation.

Cell and Tissue Regeneration

• Cell and tissue regeneration involves cell proliferation and development of mature cells from tissue stem cells, driven by growth factors.
• Restoration of normal tissue structure occurs only if residual tissue is structurally intact and undamaged.

Connective Tissue Deposition

• Connective tissue deposition occurs when repair cannot be accomplished by regeneration alone
• Replacement of injured cells with connective tissue leading to a scar or a combination of regeneration of some residual cells and scar
• After injury, a hemostatic plug of platelets forms, stopping bleeding and providing a scaffold for fibrin deposition.
• Inflammatory cells enter the wound in the next 48 hours to eliminate microbes and clear debris.
• In the days that follow epithelial, vascular, and fibroblast cells proliferate and migrate to close the wound.
• Fibroblasts lay down collagen fibers.
• Over weeks, cells form granulation tissue, filling the injury site.
• Over months, collagen slowly replaces tissue forming a stable fibrous scar. Scar tissue results in fibrosis and injury, like stroke and heart attack.

Proliferative Capacity of Cells

• Tissue regeneration or scar formation depends on proliferative capacity.

Labile Tissues

• Labile tissues' cells are continuously lost and replaced by maturation of stem cells
• Labile tissues can readily regenerate if the stem cell pool remains
• Examples include blood cells in the bone marrow, skin epithelium, and mucous membranes

Stable Tissues

• Stable tissues have limited proliferative activity in their normal state but can divide in response to injury or loss
• Most solid tissues, except heart and brain, are stable tissues

Permanent Tissues

• Permanent tissues are considered nonproliferative and postnatal

Cerebrovascular Disease (Stroke)

• Cerebrovascular disease involves an altered blood flow to the brain, leading to tissue infarction
• It can be ischemic or hemorrhagic.
• Ischemic stroke is caused by an occlusive vascular disease, usually an embolism or thrombosis.
• Hemorrhagic stroke is caused by hypertension-induced blood vessel weakening.
• Genetic predisposition to aneurysm formation and tissue damage.
• If tissue perfusion is not achieved, the affected brain part undergoes irreversible injury and liquefaction necrosis.
• Stroke is usually characterized by memory deficits, visuospatial issues, judgment, personality, motor skills, and language difficulties.

Congenital Anomalies

• Anatomic defects are present at birth with genetic or environmental causes.
• Those born with anomalies might represent a less serious developemental failure in early embryogenesis.

Trisomy 21 (Down Syndrome)

• Trisomy 21 is a the most common of syndromes affecting cells with 47 chromosomes with an extra copy of chromosome 21 as a result of meiotic nondisjunction.
• Incidence increases with increasing maternal age.
• Diagnostic clinical features (usually evident even at birth) include flat facial profile, oblique palpebral fissures, and epicanthic folds.
• Over 40 year olds develop neuropathic changes like Alzheimer's.
• Leads to severe Intellectual Disability.