Introduction to Pathophysiology (Week 3)

Homeostasis

• Homeostasis is the preservation of a constant internal environment despite a changing external environment.
• An inability to maintain homeostasis leads to pathologies, such as:
  • Thermoregulation
  • Energy balance
  • Serum glucose
  • Osmoregulation
  • Acid-Base balance
  • Blood volume

Pathophysiology

• Pathology refers to the structural and functional changes in the body caused by disease or trauma.
• Pathophysiology studies disordered physiological processes associated with disease or injury.
• Pathophysiology is the convergence of pathology and physiology.
• Pathophysiology describes conditions typically observed during a disease state.
  • For example, the pathophysiology of Parkinson's disease is the death of dopaminergic neurons.
  • As another example, the pathophysiology of heart failure is a reduction in the efficiency of the heart muscle, through damage or overloading.
• Pathophysiology seeks the underlying cause(s) (etiology) of a disease.
• Pathophysiology seeks to understand the mechanism(s) that result in the presenting signs and symptoms (pathogenesis).
• Pathophysiology seeks to:
  • Identify how both the gross and microscopic appearance (morphology) of cells and tissues differ from healthy tissue
  • Link these differences to cellular, organ and/or organ system dysfunction

Essential Definitions

• Signs are any objective evidence of a disease, such as blood in the stool, a skin rash, cough, or chest pain; they can be recognized by a doctor, nurse, family members, and the patient.
• Symptoms are subjective experiences such as stomach-ache, lower-back pain, fatigue, or chest pain, and can only be detected or sensed by the patient.
• Morphology is the study of form and structure.
• Subclinical refers to a condition not severe enough to present definite or readily observable symptoms.
• Sequelae are conditions that are the consequence of a previous disease or injury, such as Long Covid.
• Complications are medical problems that occur during a disease, or after a procedure or treatment has been completed.
• Resolution is the reduction in the severity of a pathological state.

Illness vs. Disease

• Illness is a sickness or deviation from a healthy state.
  • It has a broader, more subjective and less ominous meaning than disease.
  • Illness tends to be acute or short term.
• Disease is a biological or psychological alteration that results in organ/system dysfunction.
  • Disease tends to be chronic.
  • It is a biomedical condition substantiated by objective data.
  • Disease can occur without perceiving the presence of an illness, such as hypertension, atherosclerosis, or cervical cancer.

Acute vs Chronic Disease

• Acute disease has a rapid onset and short duration, is usually self-limiting, and typically allows full recovery with full resolution.
• Chronic disease often results in a permanent impairment or disability, requires special rehabilitation and/or long-term management, and may fluctuate in intensity with exacerbations.

Cellular Adaptations

• Atrophy is a decrease in size of cells secondary to loss of cell substances or cell number, resulting in a smaller organ/tissue; atrophy does not imply cells are dead, but they may simply have reduced functionality or number.
• Hypertrophy is the opposite of atrophy, involving an increase in the size of cells and increased size of organ; it can be physiologic or pathologic, and may affect skeletal muscle, the uterus, the myocardium, or the thyroid gland.
• Hyperplasia is an increase in cell number, leading to an increase in organ size; it can be hormonal, driven by hormones, or compensatory, driven by tissue loss or damage.
• Metaplasia is when one adult cell type is replaced by another adult cell type, arising through genetic reprogramming.
  • An example is the replacement of columnar epithelium by stratified squamous cells in the upper airways of smokers.
• Dysplasia is the presence/development of abnormal cells within a tissue or organ.
  • It is a broad/ambiguous term used in pathology and may be a precancerous condition.
  • It can be macroscopic, such as hip dysplasia, or microscopic, such as cancers.
  • Microscopic dysplasia is characterized by:
    • Cells of unequal size
    • Abnormally shaped cells
    • Cells with excessive pigmentation
    • An unusual number of cells that are dividing
    • As seen in Pap Smears (epithelial dysplasia)

Cell Injury

• Cellular consequences of an insult or injury depend on
  • Type of insult
  • Status of cells at time of insult
  • Adaptability of cells
  • Genetic makeup of cells
• Healing ideally restores the original cellular structure and function, but serious injuries may only allow connective (scar) tissue to form.
• Connective tissue provides structural integrity but lacks the original tissue's functional capacity with possible fibrosis.
• Physical therapists often want to limit this situation.
• Chaotic collagen makes for a stiff joint, requiring physical therapists to break up the scar tissue.

Mechanisms of Cell Injury:

• Mechanisms of Cell Injury include:

  • Reduced oxygen availability
  • Infectious agents
  • Aberrant immune reactions
  • Genetic abnormalities
  • Nutritional imbalance
  • Physical factors/Injury
  • Chemical Factors

• Reduced oxygen availability to the tissue:

  • Ischemia: Blood flow is below minimum necessary to maintain cell homeostasis. It can be caused by reduced blood flow or increased metabolism beyond the capacity of the vascular system to deliver the oxygen.

• Hypoxia or anoxia: Deficiency or absence of O₂. Blood flow may be adequate but O₂ content is compromised.

• Causes of reduced oxygen availability include:

  • Obstruction in moving air to lung
  • Inadequate movement of O₂ from lung to blood.
  • Inadequate transport of O2 (anemia, blockage)
  • Inability to utilize O₂ at tissue level to fuel cell processes

• Infectious agents:

  • Bacteria invade tissue and release exotoxins (released into the surrounding medium) or endotoxins (remain within the bacteria and released upon cell death).
  • Sepsis is the presence of microorganisms or their toxins in the blood
  • Septic shock: Endothelial cell damage, reduced blood volume, maldistribution of blood flow results in.

• Aberrant Immune Reaction

• Overly aggressive inflammatory response (Anaphylaxis, cancer)

• Autoimmune diseases

  • Body does not recognize its cells as “self” and mounts an immune response
    • Diabetes Mellitus
    • TB
    • RA

• Genetic abnormalities - Causes injury and death by:

  • Chromosomal damage resulting in multiple abnormalities (Downs syndrome)
  • Single mutations which change the function of a protein (Marfan's syndrome, Sickle Cell Anemia)
  • Gene mutations that interact with environmental factors to cause multifactorial disorders

• Nutritional imbalance

  • Calories: Caloric deficiencies and Caloric excess
  • Imbalance
  • Specific nutritional deficiencies such as protein (kwashiorker) iron (Anemia), Vitamin C (Scurvy), Vitamin D (bone defects)

• Physical Factors

  • Trauma (MVA, athletics, penetrating wounds)
  • Environmental Factor Extremes:
    • Cold
    • Heat (burns)
    • Radiation

• Chemical Factors

  • Chemicals that directly injure/kill cells:
    • Heavy metals (Hg), chemotherapeutic agents, CCl4
    • Chemicals whose metabolites injure/kill cells: Acetaminophen
    • Chemicals that generate reactive oxygen species i.e. oxygen free radicals or ROS: Superoxides, H₂O2, OH, NO (nitric oxide).
    • Lipid peroxidation, DNA fragmentation, Cross-linking of proteins

Cell Injury and Outcomes

• Consequences of Cell Injury

  • Cellular consequences depend on the type and duration of the injury, as well as the cell type, blood supply, nutritional and immune status of the individual

• Replication Capacity and Reversible injuries include:

  • Reversible cell injury:
    • Mild injury leads to sub lethal alterations/injury and inflammation in the affected cells with recovery resulting in a return to preinjury state
  • Chronic adaptation allows for functions in an altered environment
    • Occurrence of sublethal stress
    • Cell adaptation
    • Atrophy, hypertrophy, hyperplasia, metaplasia
  • Irreversible cell injury is synonymous with death.

Cell Death

• Apoptosis: a natural, well regulated, and useful process. (Cell death)
  • Plays an important role in embryogenesis and housekeeping.

Necrosis

• Necrosis: a form of tissue injury that results in cell death within is caused by external factors like infection, toxins, or trauma.
  • It results in a unregulated digestion of cell components, uncontrolled release of products into the extracellular space, and initiates an inflammatory response.
  • Normal housekeeping does not occur and results in the accumulation of decomposing cells and debris.
  • Classic example is gangrene and requires surgical removal (Debridement).