Pathology: Understanding Cellular Injury

• BMS 151 covers the foundations of pathology, focusing on cellular and tissue responses to injury.
• The lecture includes information from Dr. Mie Ali and Dr. Mona Younis, Professors of Pathology.

Case Scenario: Ali, a 44-year-old man

• Ali has a history of poorly controlled diabetes mellitus.
• He experiences vague abdominal pain.
• Ultrasound reveals an enlarged liver with a preserved shape and smooth outer surface.
• Ali denies alcohol or drug intake, except for insulin.
• The doctor suggests the liver could return to normal size with proper blood glucose control.
• Questions for the case:
  • What caused Ali's enlarged liver?
  • Is Ali's case reversible?
  • What are the microscopic types of this disease?

Cell Injury: Definition

• Cell injury involves a variety of structural and functional changes in cells due to external or internal environmental changes that alter homeostasis.
• Normal cell's ability is to maintain stable physiologic functions via homeostasis.
• Cellular dysfunction leads to organ dysfunction, resulting in clinical expression.

Cell Injury: Causes ("Injurious Agents")

• Hypoxia (low tissue oxygen) is the most common cause of cell injury.
• Nutritional disturbances occur as either excesses, as in obesity, or deficiencies, as in wasting diseases like diabetes mellitus, tuberculosis, and cancer.
• Physical agents include trauma, heat, cold, and radiation.
• Chemical agents include concentrated acids, alkalies, poisons (e.g., CCl4, cyanide), and drugs.
• Infectious agents include viruses, bacteria, and fungi.
• Immunologic reactions causing autoimmune diseases also result in cell injury.

Cell Injury: Effects

• The effects of cell injury depend on the nature, duration, and severity of the injurious agents.
• Effects also depend on the type and state of the injured cell.
• Brain tissue is very sensitive to hypoxia (2-5 minutes).
• Skeletal muscles can adapt to hypoxia for 2-6 hours.
• Injury can result in cellular adaptation, reversible cell injury, irreversible cell injury, or intracellular/extracellular accumulations.

Chart flow of Cell Injury

• Normal cells, when exposed to stress or injurious agents adapt to their new environment or begin to sustain injury.
• Metabolic derangements can lead to the accumulation of certain tissues - Tissue accumulation.
• Cells that sustain minor or transient injuries go through reversible injury.
• Cells that undergo severe progressive injury go through irreversible cell injury which leads to necrosis or apoptosis.

Cellular Adaptation

• Cellular adaptation is modification of cell structure and function in response to stress to preserve cell vitality.
• It is a reversible process.
• Exceeding the cell's adaptive capacity leads to cell injury.
• Types of Adaptation: Atrophy, Hypertrophy, Hyperplasia and Metaplasia.

Atrophy

• Atrophy is a decrease in the size of a mature organ due to a decrease in cell size and/or number.
• Cells become smaller due to decreased protein synthesis and increased protein breakdown.
• Physiological examples include aging, uterus atrophy after labor, and thymus atrophy after puberty.
• Pathological examples include disuse atrophy after bone fracture, neurogenic atrophy due to denervation, and ischemic atrophy.

Hypertrophy

• Hypertrophy is an increase in the size of a mature organ due to an increase in cell size.
• Increased synthesis of structural proteins can cause the cells to get larger due to Increased functional demand, growth factor stimulation, and hormonal stimulation.
• Physiological hypertrophy includes the smooth muscle of the uterus during pregnancy and skeletal muscle hypertrophy in athletes.
• Pathological hypertrophy example is cardiac muscle hypertrophy of the left ventricle in systemic hypertension.

Hyperplasia

• Hyperplasia is an increase in the size of a mature organ due to an increase in cell number.
• Cell proliferation is due to increased functional demand, growth factor stimulation, and hormonal stimulation.
• Physiological hyperplasia occurs in the female breast during puberty, pregnancy, and lactation.
• Pathological hyperplasia occurs in bone marrow after hemorrhage, skin around wounds, liver cells after partial destruction, and the prostate and endometrium under hormonal stimulation.

Metaplasia

• Metaplasia is when one type of tissue changes into another type of the same category (epithelium to epithelium; connective tissue to connective tissue).
• It is always pathological.
• It is reversible.
• It is caused by the reprogramming of stem cells that differentiate along a new pathway to tolerate stress.
• Examples include:
  • Squamous metaplasia respiratory epithelium in smokers.
  • Squamous metaplasia of th urinary bladder in bilharziasis.
  • Intestinal metaplasia of esophagus in reflux esophagitis (Barrett's esophagus).

Cell Injury (Reversible vs. Irreversible)

• Reversible (Sub-lethal) "Degeneration:" It is caused by a mild injurious agent of short duration.
  • Affects active parenchymatous cells with lots of mitochondria.
  • Functional and morphological changes are reversible if the damaging stimulus is removed.
  • Includes cloudy swelling & hydropic degeneration and fatty change.
• Irreversible (Lethal): It is caused by a severe injurious agent of long duration.
  • Any cell can be affected by the irreversible.
  • Functional and morphological changes are irreversible if the damaging stimulus is removed.
  • Includes Necrosis (death of a group of cells) and Apoptosis (death of a single cell).

Reversible Cell Injury "Degeneration"

• Cloudy Swelling & Hydropic Degeneration is a is a form of reversible cell injury characterized by intracellular water accumulation which is:
  • mild in cloudy swelling.
  • can be excessive in hydropic degeneration.
• The earliest type of cell injury is cloudy swelling.
• Caused by mild injury of short duration Pathogenesis:
  • Mitochondrial injury occurs first leading; Decreased ATP>
  • Decreased Na/K pump → entry of Na inside the cell.
  • Anaerobic respiration → Lactic acid accumulation.
  • Release of mitochondrial protein within cytoplasm.
  • All these → increase in the cytoplasmic osmotic pressure helps intra-cellular water accumulation → cell swelling
• Morphology of the kidney, the affected organ in this case, appears as an enlarged organ, maintains it's natural shape, with a smooth surface. It is pale due to compression of the capillaries by the swollen cells, the capsule is stretched to contain the enlarged organ, it is soft and the inside appears cloudy, opaque and appears to be bulging outwards.
• Microscopic appearance of:
  • Cloudy swelling: The cells are swollen with compressed capillaries between. The nucleus is normal and the cytoplasm is granular.
  • Hydropic degeneration: The cells are swollen with compressed capillaries between. The nucleus is normal and the cytoplasm is pale and shows multiple vacuoles.
• Most prominently shown in the kidney's proximal convoluted tubules and it's rich mitochondria.

Fatty Change [steatosis]

• It is reversible cell injury by intracellular accumulation of neutral fat.
• The liver is the most commonly affected organ.
• Grossly, the liver is enlarged, the shape is preserved, the surface remains smooth, the new color is now yellow, the capsule is stretched, the consistency is soft, and the cut surface is yellow and greasy to the touch.
• Microscopically: The cells are swollen capillaries in between. The nucleus is normal.
• The cytoplasm varies depending on when you catch it:
  • Early: multiple tiny cytoplasmic clear vacuoles. Later: fat globules forming a big globule that pushes and flattens the nucleus against the cell membrane giving the cell a signet ring appearance.
• Fat special stains are done on frozen sections

Identification of Fatty Change

• Dx & E Stain
• Osmium acid turns black.
• Sudan III turns orange
• Oil red O turns red.

Review Questions

• What is the scientific term for when a mature organ decreases in size because the organ’s cells has decreased?
• What is the scientifics name the increase in the size of mature by a higher number of cells?
• What is the scientific name of the reversible cell injury characterized by mild intercellular water accumulation?
• The enlargement of the female breast at puberty is an example of what?
• Metaplasia is what kind of process? A pathologic, long winded or reversible process?
• What is earliest type of cell injury due to lack of oxygen?