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$$$CCL_4$$), 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$$$O_2$$ 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^+$$$Na^+/K^+$$ 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^{++}$$$Ca^{++}$$ 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