PHA 334 - Lecture #1 (Introduction)

Pathophysiology

The study of how disease or injury affects normal physiological processes and disrupts homeostasis

Pathology

The study of disease

Disease

An abnormal alteration in body structure or function that produces specific signs or symptoms

Cell injury

Damage to a cell caused by internal or external factors that disrupt homeostasis

Cellular susceptibility to injury

The likelihood that a cell will be damaged based on its characteristics

Cell specialization

Highly specialized cells with enzyme-rich or specialized organelles are more susceptible to injury

Cell regenerative ability

Cells that can divide and regenerate recover better from injury than cells that cannot

Low regenerative capacity example

Cardiac muscle cells

High regenerative capacity example

Skin cells

External injurious agents

Factors outside the body that cause cell injury

Exogenous toxins

Toxic substances originating outside the body

Heavy metals

Exogenous toxins such as lead and mercury

Caustic agents

Exogenous chemicals such as acids and bases that cause tissue damage

Plant toxins

Natural toxins from plants such as poison ivy (exogenous toxins)

Animal toxins

Toxins from animals such as venom from a snake bite (exogenous toxins)

Infectious agents

Pathogens that injure cells including bacteria, viruses, parasites, and fungi (exogenous toxins)

Radiation

External energy exposure that damages cellular DNA and proteins (exogenous toxins)

Physical trauma

Mechanical forces that cause tissue and cell injury

Pressure injury

Tissue damage caused by prolonged pressure such as sitting or lying down for a long time (Physical trauma)

Mechanical injury

Injury from strong physical force such as a blow or car accident (Physical trauma)

Thermal injury

Injury caused by extreme temperatures (Physical trauma)

Burns

Thermal injury caused by excessive heat (Physical trauma)

Frostbite

Thermal injury caused by extreme cold (Physical trauma)

Internal injurious agents

Factors within the body that cause cell injury

Ischemia

Decreased blood flow resulting in reduced oxygen and nutrient delivery (Internal injurious agents)

Hypoxia

Reduced oxygen availability to cells (Internal injurious agents)

Endogenous toxins

Toxic substances produced within the body (Internal injurious agents)

Free radicals

Reactive molecules that damage cellular components (Internal injurious agents)

Genetic factors

Mutations or abnormalities affecting cell structure or function (Internal injurious agents)

Immunologic factors

Autoimmune reactions that damage cells (Internal injurious agents)

Cellular adaptations

Structural or functional changes that allow cells to survive injury

Hyperplasia

Increase in the number of cells due to abnormal stimulation

Hyperplasia example

Endometrial proliferation due to prolonged estrogen exposure

Hypertrophy

Increase in cell size due to increased functional demand

Hypertrophy example

Enlargement of the heart due to aortic stenosis

Atrophy

Decrease in cell size due to reduced blood supply, disuse, or denervation

Atrophy example

Kidney atrophy due to renal artery atherosclerosis

Metaplasia

Reversible change from one differentiated cell type to another

Metaplasia example

Replacement of esophageal squamous epithelium with glandular epithelium in acid reflux

Dysplasia

Disordered cellular growth with abnormal size, shape, and organization

Dysplasia significance

Considered a precursor to cancer

Reversible cell injury

Early cellular damage that can be reversed if the stressor is removed

This can occur through hydropic sweeling

Hydropic swelling (Reversible cell injury)

Accumulation of water in the cell due to failure of ion pumps

Organelle swelling (Reversible cell injury)

Swelling of mitochondria and endoplasmic reticulum during reversible injury

Irreversible cell injury

Damage beyond recovery that leads to cell death

• The exact ‘point of no return’ is not defined; however, irreversible injury is characterized by:

– Severe swelling or rupture of cell

– Breakdown of organelles

– Nuclear changes

– Can lead to necrosis: one type of cell death in the living body

Irreversible injury features

• The exact ‘point of no return’ is not defined; however, irreversible injury is characterized by:

– Severe swelling or rupture of cell

– Breakdown of organelles

– Nuclear changes

– Can lead to necrosis: one type of cell death in the living body

Pyknosis (Irreversible injury)

Nuclear shrinkage and chromatin condensation

Karyorrhexis (Irreversible injury)

Nuclear fragmentation

Karyolysis (Irreversible injury)

Loss of the nucleus

Ischemic cell injury mechanism (Necrosis)

Decreased oxygen leads to decreased ATP production

ATP depletion effect (Necrosis)

Failure of Na⁺/K⁺ and Ca²⁺ pumps (causing Influx of Na and Ca/efflux of K)

Ion imbalance (Necrosis)

Influx of Na⁺ and Ca²⁺ and efflux of K⁺

Cell swelling mechanism (Necrosis)

Water follows sodium into the cell causing hydropic swelling

Anaerobic metabolism consequence (Necrosis)

Lactic acid accumulation and decreased cellular pH

Final outcome of ischemic injury (Necrosis)

Organelle damage leading to necrosis

Necrosis (Irreversible injury)

Uncontrolled cell death caused by severe injury

Necrosis characteristics

• Damage to cell causes rupture of cell membrane

• Intracellular contents are expelled into the extracellular space

• This triggers inflammation

• Necrosis usually involves large numbers of cells

Coagulative necrosis (Form of Necrosis)

Protein denaturation with preserved tissue architecture

Caused by: local ischemia, mild burns produced by heat, electricity

Coagulative necrosis causes (Form of Necrosis)

Local ischemia or mild burns

Caseous necrosis (Form of Necrosis)

Cheese-like mixture of proteins and lipids

Caused by: tuberculosis, syphilis, certain fungi

Caseous necrosis causes (Form of Necrosis)

Tuberculosis, syphilis, certain fungal infections

Gangrene necrosis (Form of Necrosis)

Tissue death due to loss of blood supply (two types: wet and dry)

Wet gangrene (Form of Necrosis)

Gangrene with bacterial infection

Dry gangrene (Form of Necrosis)

Gangrene with little or no infection

Liquefactive necrosis (Form of Necrosis)

Rapid dissolution of dead cells into liquid

– Cells dissolve, leaving a fluid filled cavity

– Caused by: bacterial, sometimes fungal infections; in the brain, cerebral artery occlusion can cause it

Liquefactive necrosis causes (Form of Necrosis)

Bacterial infections or cerebral artery occlusion in the brain

Apoptosis

Programmed and regulated cell death

It is a highly ordered process that minimizes potentially damaging responses of the host

– With apoptosis, inflammation is not initiated

• Induced by:

– Normal physiology, for example, maintenance of organs

– DNA damage, misfolded proteins, among other factors

Apoptosis inflammation

Does not trigger inflammation

Apoptosis triggers

DNA damage, misfolded proteins, normal tissue maintenance

During this Apoptosis process:

• Caspases are activated; they are a special group of enzymes that carry out the cell’s death

• Changes in cell morphology:

– Shrinkage of the cytoplasm

– Condensation and cleavage of nucleus (these nuclear changes are similar to necrosis)

• Formation of apoptotic bodies

– Membrane-bound bodies that contain organelles (organelles may still be functional)

– Phagocytized

• One or a few cells undergo apoptosis, not large groups of cells

Caspases

Enzymes that execute apoptosis

Apoptotic cell changes

Cell shrinkage, nuclear condensation, apoptotic body formation

Apoptosis scope

Affects one or a few cells at a time

Necrosis vs apoptosis

Necrosis is uncontrolled and inflammatory; apoptosis is controlled and noninflammatory

Etiology

The cause or origin of a disease

Categories:

1. Acquired

2. Idiopathic

3. Congenital

4. Genetic (chromosomal or monogenic/mendalin)

5. Multifactorial

Genetic etiology

Disease caused by mutations in DNA

Mutations or variations in DNA

• Chromosomal: abnormalities in chromosomes (e.g., structural or numeric)

• Monogenic/Mendelian

– Autosomal dominant

– Autosomal recessive

– X-linked

Single Gene, Autosomal Dominant Disorder

General characteristics:

• Single gene variation (mutation) in an autosome

– Males and females are equally affected

• An individual who inherits one copy of the gene variation will have the disease

• Usually successive generations are affected, the disease does not occur in the offspring of unaffected individuals

Example: Huntington’s Disease

Single Gene, Autosomal Recessive Disorder

General characteristics

• Single gene variation (mutation) in an autosome

– Males and females are equally affected

• An individual who inherits two copies of the gene variation will have the disease

• Carriers have one copy of the gene variation and can pass the gene variation to offspring

– Carriers are usually clinically healthy

• Seems to skip generations

Example: Sickle Cell Anemia

Single Gene, X-linked Disorder

General characteristics

• Single gene variation (mutation) in an X chromosome

– A male who inherits the gene variation will have the disease

– Males are affected more than females

– No father-to-son transmission of the gene variation

• Daughters of an affected male are carriers of the gene variation and can pass it to offspring

– Daughter could be an asymptomatic carrier, or daughter could have variable symptoms of the disease

• Seems to skip generations

Example: Hemophilia

Genetic etiology example

Sickle cell anemia

Congenital etiology

Disease present at birth due to developmental defects

Congenital etiology example

Spina bifida

Acquired etiology

Disease that develops after birth

Acquired etiology example

AIDS

Idiopathic etiology

Disease with no known cause

Idiopathic etiology example

Idiopathic pulmonary fibrosis

Multifactorial etiology (Disease)

Genetic background, environmental factors, lifestyle contribute to the

pathogenesis of the disease

Multifactorial etiology example

Type 2 diabetes

Pharmacology

The study of drugs and their interactions with living systems through chemical processes

Therapeutics

The use of interventions to treat disease

Pharmacotherapy

– Drugs to treat disease or injury

• In general, drugs may replace, mimic or block the action of an endogenous substance or process

Chemotherapy

Drugs that eradicate foreign or rapidly dividing cells

Symptoms

Subjective experiences reported by the patient

Signs

Objective findings observed or measured by a clinician

Diagnosis

Identification of a disease based on signs, symptoms, and tests

Prognosis

Predicted outcome or course of a disease

Therapeutic intervention

Any method used to treat or manage disease (ex: Surgery, Radiation, Genetic, Immunological)

Surgical therapy

Treatment involving operative procedures

Radiation therapy

Treatment using ionizing radiation

Genetic therapy

Treatment targeting genetic material