Cell injury

What is cell injury?

Structural, functional, and biochemical abnormalities in one or more essential cell components

What determines the cellular response to an injurious stimulus?

The type of stimulus, its duration, and its severity

What determines the consequences of cell injury?

The type, state, and adaptability of the injured cell

What is the most common cause of cell injury?

Hypoxia/ischaemia (oxygen and nutrient deprivation)

What does hypoxia/ischaemia lead to?

Reduced ATP production

Name causes of hypoxia

Cardiorespiratory failure, decreased oxygen-carrying capacity of blood (anaemia), carbon monoxide poisoning

How does carbon monoxide cause hypoxia?

It forms stable carboxyhaemoglobin that blocks oxygen carriage

Name physical agents that cause cell injury

Extremes of temperature, sudden changes in atmospheric pressure, radiation, electric shock

Name chemical agents/drugs that cause cell injury

Poisons (arsenic, cyanide, mercuric salts), pollutants/insecticides/herbicides, industrial hazards (CO, asbestos), alcohol, therapeutic drugs

Name infectious agents that cause cell injury

Viruses, rickettsiae, bacteria, fungi, parasites

Name immunologically mediated causes of cell injury

Autoimmune reactions, hypersensitivity reactions

Name genetic causes of cell injury

Chromosomal abnormalities, DNA defects

Name nutritional causes of cell injury

Protein-energy malnutrition (kwashiorkor), total energy malnutrition (marasmus), excessive nutrition (obesity), anorexia nervosa

What are the two morphologic classifications of cell injury?

Reversible (sublethal/nonlethal) and irreversible (lethal)

Define reversible cell injury

Abnormalities that revert to normal once the injurious stimulus is removed

Define irreversible cell injury

Damage beyond repair; the cell does not recover even after the stimulus is removed

What two features of reversible cell injury are seen on light microscopy?

Cellular swelling and fatty change

What causes cellular swelling?

Failure of energy-dependent ion pumps in the plasma membrane, causing loss of ionic and fluid homeostasis

What is the mechanism of cellular swelling in ischaemia/hypoxia?

Breakdown of the ATP-dependent sodium pump leads to sodium (and water) influx and potassium outward diffusion

What are other names for generalized cellular swelling?

Hydropic change, ballooning change, vacuolar degeneration

Name ultrastructural (EM) changes seen in cellular swelling

Plasma membrane blebbing/blunting/microvilli loss; mitochondrial swelling with amorphous densities; ER dilation with polysome detachment (myelin figures); nuclear disaggregation of granular/fibrillar elements

What is parenchymal cell fatty change?

Accumulation of excess triglyceride, mainly in liver and heart muscle cells

Name the two sources of fat delivered to liver cells

Chylomicrons from small intestinal epithelium; non-esterified free fatty acids (NEFA) from adipose tissue lipolysis

When does steatosis (fatty change) develop?

Increased fatty acid intake, reduced fatty acid oxidation, or reduced apoprotein synthesis impairing lipid removal from the cell

What are the two consistent features of irreversible cell injury?

Inability to reverse mitochondrial dysfunction (no oxidative phosphorylation/ATP) and profound disturbances in membrane function

What results from injury to lysosomal membranes?

Enzymatic dissolution of the injured cell (cell death)

What are the major causes of ATP depletion?

Reduced oxygen/nutrient supply, mitochondrial damage, and toxins (e.g., cyanide)

What happens when the plasma membrane Ca2+ pump fails?

Influx of Ca2+ with damaging effects on numerous cellular components

What happens to ribosomes and the ER when ATP is reduced?

Ribosomes detach from the rough ER and polysomes dissociate, reducing protein synthesis

What is the mitochondrial permeability transition pore?

A high-conductance channel in the mitochondrial membrane that causes defective oxidative phosphorylation

What does leakage of cytochrome c from mitochondria cause?

It may induce cell death

What are the effects of increased intracellular Ca2+?

Opens the mitochondrial permeability transition pore (impairing ATP synthesis), activates phospholipases/endonucleases/proteases, and activates caspases leading to cell death

Name sources of oxygen-derived free radicals

Oxidation-reduction reactions (e.g., ischaemic reperfusion), radiant energy absorption (UV, x-rays), activated leukocytes in inflammation, enzymatic metabolism of drugs/chemicals, transition metals (iron, copper)

What damage do free radicals cause?

Lipid peroxidation of membranes, oxidative modification of proteins, DNA strand breaks/cross-linking/adduct formation

What happens when DNA damage is too severe to repair?

The cell initiates a suicide program resulting in death by apoptosis

What is an intracellular accumulation?

Abnormal accumulation of substances within a cell, typically in response to sub-lethal injury

Name the two categories of intracellular accumulations

Endogenous and exogenous

Give examples of endogenous normal constituents that accumulate

Water, protein (hyaline droplet change), lipid (fatty change), carbohydrates

Give an example of exogenous accumulation

Non-metabolised particles, e.g., carbon, silica, products of infectious agents

Name the four types of abnormalities causing intracellular accumulations

Inadequate rate of metabolism; defects in protein folding, transport, and degradation; metabolic enzyme defects; deposition with inability to degrade/remove

Name the main categories of substances that accumulate intracellularly

Lipids, proteins, glycogen, pigments

What is atherosclerosis, in terms of lipid accumulation?

Foamy macrophages accumulating lipid in blood vessel walls

What are xanthomas?

Foamy macrophages accumulating lipid in the skin and tendons

What is cholesterolosis?

Foamy macrophages accumulating lipid in the mucosa of the gall bladder

What stains demonstrate lipid accumulation?

Oil red O, Sudan stains, osmium tetroxide

Give an example of a disease caused by defective protein transport/secretion

Alpha1-antitrypsin deficiency (accumulation of partially folded intermediates); cystic fibrosis

Give examples of cytoskeletal or aggregated protein accumulation diseases

Alzheimer's disease (microtubules/filaments); some forms of amyloidosis (aggregation of abnormally folded proteins)

What causes glycogen storage diseases?

Enzymatic defects in glycogen synthesis or breakdown

Where does glycogen accumulate in diabetes mellitus?

Distal renal tubules and liver cells

How does accumulated glycogen appear histologically, and what stain demonstrates it?

Clear cytoplasmic vacuoles (dissolves in processing reagents); demonstrated with periodic acid-Schiff (PAS) stain

What is anthracosis?

Exogenous accumulation of carbon (coal dust) pigment, classically in the lungs

What is lipofuscin?

A "wear and tear" lipochrome pigment; a polymer of lipids, phospholipids, and protein with perinuclear location; yellow-brown; demonstrated with long Ziehl-Neelsen stain

What is melanin and how is it demonstrated?

A brown-black pigment formed in melanocytes; demonstrated with Schmorl's, Masson-Fontana, or Turnbull blue stains

What is haemosiderin and how is it demonstrated?

A pigment derived from haem via ferritin micelles (e.g., seen in a bruise); demonstrated with Perl's Prussian blue reaction

What causes jaundice?

Excess bilirubin from red blood cell breakdown

What is ochronosis?

Accumulation of homogentisic acid in skin, connective tissue, and cartilage, occurring in alkaptonuria

What is pathological calcification?

Abnormal deposition of calcium salts with smaller amounts of iron, magnesium, and other mineral salts

Define dystrophic calcification

Calcification occurring locally in non-viable/dying tissue with normal serum calcium and no derangement of calcium metabolism

Define metastatic calcification

Calcium deposition in viable tissues, associated with hypercalcaemia and derangement of calcium metabolism

Name sites of dystrophic calcification

Areas of necrosis (coagulative, caseous, liquefactive, fat necrosis), atheromatous plaques, aging/damaged heart valves, vessel walls in the elderly

Describe the macroscopic and microscopic appearance of dystrophic calcification

Macroscopic: fine white gritty granules/clumps; Microscopic (H&E): haematoxyphilic deposits

Name causes of hypercalcaemia leading to metastatic calcification

Increased PTH secretion (parathyroid tumours/ectopic), bone destruction (tumours, Paget's disease), vitamin D disorders (intoxication, sarcoidosis), renal failure (phosphate retention/secondary hyperparathyroidism), aluminium intoxication, milk-alkali syndrome

Name common sites of metastatic calcification

Gastric mucosa, kidneys, lungs, systemic arteries, pulmonary veins

What is the composition of metastatic calcification deposits?

Noncrystalline amorphous or hydroxyapatite crystals, morphologically similar to dystrophic calcification