Patho Lecture 2

Principles of Pathophysiology

Basic Terms and Definitions

• Etiology: The cause of the disease.
• Pathogenesis: The mechanism of development of the disease.
• Manifestation: The signs and symptoms of the disease.
• Progression: How the disease advances.
• Diagnosis: Identifying the disease.
• Treatment: Addressing the disease.
• Prognosis: Expected outcome of the disease.

Physical Description Terminology:

• Focal vs. Diffuse: Whether the disease is localized or widespread.
• Microscopic vs. Macroscopic (Gross): Level of detail viewable with or without a microscope.
• Eosinophilic vs. Basophilic: Staining characteristics of tissues.
• Hyaline: A glassy, translucent appearance.
• Endogenous vs. Exogenous: Originating from within or outside the body.
• Morbidity vs. Mortality: Illness vs. death rates.
• Co-morbidity: Presence of multiple diseases.

Cellular Adaptations to Injury/Stress

• Cells respond to stimuli via:
  • Cellular adaptation
  • Reversible cell injury
  • Irreversible cell injury (= cell death)

Factors Influencing Adaptation:

• Potential for cell regeneration
  • Labile cells: Continuously renewing (e.g., skin, GI tract)
  • Stable cells: Can expand if needed (e.g., liver, kidney)
  • Permanent cells: Cannot regenerate (e.g., neurons, cardiac muscle)
• Severity of Injury
• Duration of Injury
• Condition of the Cell
• Location of the Cell
• Degree of Cell Specialization

Mechanisms of Cellular Adaptation

Atrophy

• Shrinkage of cell/organ due to loss of organelles.
• Adaptation to decreased need/resources.
• Involves changes in both production and destruction of cellular constituents.
• A reversible restructuring to facilitate survival under diminished use.
• Types:
  • Physiological: Normal loss of endocrine stimulation.
  • Pathological: Diminished blood supply, inadequate nutrition, loss of innervation, abnormal loss of endocrine stimulation, decreased workload.

Hypertrophy

• Increase in cell size and functional capacity.
• Due to increased production/number of intracellular organelles (increased metabolic demands/hormonal stimulation).
• Types:
  • Physiological: Increased functional demand (e.g., muscle growth with exercise).
  • Pathological: Goiter, endocrine gland hyperactivity, hormone-secreting tumor, excessive organ demand (e.g., myocardial hypertrophy due to valve damage/hypertension).

Hyperplasia

• Increase in organ/tissue size due to an increase in the number of cells.
• Due to increased functional/metabolic demands or compensatory proliferation.
• Types:
  • Physiological: Hormonal stimulation (lactating breast), increased RBCs at high altitude.
  • Pathological: Endometriosis, psoriasis, liver regeneration following damage.

Metaplasia

• Change in which one terminally differentiated cell type is replaced by another.
• Response to persistent injury/irritation.
• Commonly, glandular epithelium is replaced by squamous epithelium.
• Not restricted to squamous differentiation.
  • Squamous metaplasia (bronchus, bladder)
  • Barrett's Esophagus.
  • Myositis ossificans.

Dysplasia

• Disordered growth and maturation of cellular components in a tissue.
• Loss of uniformity of individual cells and their architectural orientation.
• Response to persistent injurious influence; usually regresses if the influence is removed.
• A pre-neoplastic lesion; a necessary stage in cancer development.
• Dysplasia, hyperplasia, and metaplasia (not atrophy and hypertrophy) may give rise to neoplasia.
• Severe dysplasia is an indication for aggressive preventive therapy.

Intracellular Accumulations

• Accumulation of materials within a cell/organ.
  • Normal cellular constituent (e.g., water, lipids, proteins, carbohydrates)
  • Abnormal substance (e.g., products of abnormal metabolism)
  • Pigment (e.g., carbon, bilirubin)

Features of Intracellular Accumulations:

• Substances may accumulate transiently or permanently.
• Substances may be harmless or toxic.
• Location can be within the cytoplasm (lysosomes) or nucleus.
• Accumulation causes:
  • Increased production
  • Decreased metabolism
  • Increased deposition
  • Decreased transport

Examples of Intracellular Accumulations:

• Steatosis
• Hydropic change
• Pigments
• Proteins
• Glycogen
• Cholesterol

Steatosis:

• Accumulation of triglycerides within parenchymal cells.
• Most common organ involved: liver.
• Causes: protein malnutrition, toxins (alcohol, carbon tetrachloride CCL_4), obesity, anoxia.

Cellular Swelling (Hydropic Change)

• Increase in water accumulation within parenchymal cells.
• Most common cause: Loss of ATP, resulting in failure of the sodium-potassium ATPase pump.
• Water accumulation within cytoplasm and cytoplasmic organelles.

Pigment Accumulation: Hemosiderin

• Accumulation of iron within parenchymal cells and interstitium; golden-brown granules.
• Localized: hemosiderosis (common bruise from hemoglobin breakdown)
• Systemic: systemic hemosiderosis (blood transfusions, hemolytic anemias), hemochromatosis (increased iron absorption, genetic).

Pigment Accumulation: Lipofuscin

• "Wear and tear pigment."
• Indigestible mixture of lipids and proteins, a result of oxidative stress.
• Increases with age.

Accumulations: Glycogen

• Accumulation may be normal or abnormal.
• Enzyme deficiency may lead to glycogen storage diseases:
  • Pompe
  • McArdle
  • Cori
  • Von Gierke

Cholesterol

• Can accumulate in macrophages and vascular smooth muscle cells within blood vessel walls = atherosclerosis.
• Disorders of cholesterol accumulation: Xanthomas.

Causes of Cell Injury

• Hypoxia: Ischemia or decreased O_2 carrying capacity of blood.
• Physical Agents: Trauma, temperature extremes, radiation, shock.
• Chemical Agents and Drugs: Biological agents, poisons/pollutants, industrial hazards, social and therapeutic drugs.
• Infectious Agents
• Immunological Reactions
• Genetic Defects
• Nutritional Imbalances

Cell Injury: Universal Biochemical Themes

Lack of oxygen (or oxygen excess) = Decrease synthesis of ATP

Increases in intracellular calcium and loss of calcium homeostasis = activation of Calcium-dependent enzymes

Depletion of ATP = loss of membrane function and intracellular processes

Defects in membrane permeability

Reversible vs. Irreversible Cell Injury: Morphological Patterns

Reversible Injury:

• Subcellular Changes Occur in Reversibly Injured Cells:
  • Cellular swelling: Loss of activity of Na^+/K^+ ATPase pump activity = ion influx.
  • Steatosis (fatty change): Altered metabolism/transport of triglyceride.
• These forms of reversible injury MAY become irreversible.

Irreversible Cell Injury:

• Vacuolization of the mitochondria.
• Rupture of lysosomes (i.e., Lactate dehydrogenase, creatine kinase).
• Nuclear changes:
  • Pyknosis: Small, shrunken, and dark.
  • Karyorrhexis: Fragmented.
  • Karyolysis: Faded.

Important Pathway of Irreversible Injury: Hypoxic/Ischemic Injury

• Compromised aerobic respiration.
• Increased rate of anaerobic glycolysis.
• Decreased cellular pH.
• Acute cellular swelling.
• Detachment of ribosomes from RER.
• Mitochondrial swelling.
• Severe mitochondrial vacuolization.
• Lysosomal membrane rupture/activation of Ca^{++} dependent enzymes.

Free Radical Induced Injury

• A final common pathway in a variety of cell processes.
  • Chemical and radiation injury, cellular aging, oxygen toxicity, microbial killing by phagocytes.
• Consist of chemical species which are highly reactive, autocatalytic, and unstable.
• Damage involves:
  • Lipid peroxidation of cell membranes.
  • Oxidative modification of cellular proteins.
  • Damage to cellular DNA.

Fenton and Haber-Weiss Reactions

The equations:
Fe^{2+} + H2O2 \rightarrow Fe^{3+} + OH^- + \cdot OH

H2O2 + Fe^{3+} \rightarrow Fe^{2+} + \cdot OOH + H^+

Important Free Radicals

Genetic and Congenital Defects

Chromosomal Abnormalities

• Aneuploid, monosomy, trisomy, etc.

Trisomy 21: Down Syndrome

• Decreased IQ
• Simian crease
• Protruding tongue, epicanthic folds
• Tetrology of Fallot (congenital heart anomaly)

Trisomy 18: Edwards Syndrome

• Severe cardiac malformations
• “Rocker-bottom feet”, clenched hands, low-set ears
• Majority die within 1 year

Trisomy 13: Patau Syndrome

• Severe cognitive and growth delay
• Cleft lip and palate
• Nervous system and cardiac malformations

Cri-du-chat syndrome

• 5p- (5p minus) syndrome characterized by deletion of portion of the p-arm on chromosome 5.
• Infants possess high-pitched cry that sounds like that of a cat.
• Disorder is characterized by intellectual disability and delayed development, microcephaly, low birth weight, and weak muscle tone (hypotonia) in infancy
• Distinctive facial features: widely set eyes (hypertelorism), low-set ears, a small jaw, and a rounded face.
• Several organ defects as well

Kleinfelter Syndrome: (47, XXY)

• Males possessing 1 Y and more than 1 X chromosome
• Male hypogonadism and infertility-lack of androgens
• Tall, thin, relatively long legs
• High-pitched voice, gynecomastia

Turner Syndrome (45, X) or (X, O)

• Females with primary amenorrhea and sterility
• Short stature, with webbed neck

Inborn Errors of Metabolism

Lesch–Nyhan syndrome

• X-linked deficiency of deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
• Causes accumulation of uric acid in body fluids (associated with gout and kidney dysfunction)
• Neurological signs include poor muscle control cognitive disability in first year of life.
• Second year of life is characterized by self-mutilating behaviors, characterized by lip and finger biting.
• Basal ganglia damage leads to writhing movements
• Poorly utilization of vitamin B12 may lead to megaloblastic anemia.

Inborn Errors in Amino Acid Metabolism

Phenylketonuria PKU

• Autosomal recessive deficiency of the hepatic enzyme phenylalanine hydroxylase.
• High circulating levels of phenylalanine which leads to progressive mental deterioration in the first few years of life.
• Affected infants appear normal at birth, but mental retardation is evident within a few months.
• Infants tend to have fair skin, blond hair and blue eyes, because the inability to convert phenylalanine to tyrosine leads to reduced melanin synthesis.
• Exude a “mousy” or “musty” odor, due to production of phenylacetic acid
• Phenylalanine-restricted diet

Alkaptonuria (Ochronosis)

• Defect in the enzyme homogentisate 1,2-dioxygenase (HGD), which participates in tyrosine degradation.
• Urine demonstrates oxygenation of homogentisic acid
• May lead to a degenerative arthropathy

Miscellaneous Features of Cell Injury: Calcification

• Is a normal or abnormal process
• Within pathology implies the abnormal deposition of calcium salts in soft tissues
  • Dystrophic calcification; calcium deposition in dead (necrotic) / non- viable tissue
  • Metastatic calcification; calcium deposition in normal tissues due to hypercalcemia