General Pathology
Raghib Siddiqui, Arjun Ajithan
Disease– structural and functional disturbances, which cause pain and/or decrease quality of life
The main aspects of a disease process are Etiology, Pathogenesis, Molecular and Morphologic changes and Clinical Significance
Major etiologic factors are Intrinsic/Genetic or Acquired (exogenous and endogenous) factors.
Intrinsic factors– result from DNA abnormalities and may be congenital or post-natal.
Acquired exogenous factors – Deficiency, Physical factors (trauma, temp., electricity, radiation), Chemical Factors, Biological agents (viruses, bacteria, fungi parasites), Immunological factors and Psychogenic factors
Acquired endogenous factors – Genetic disorders, hormonal disturbances and immune factors and allergy
Pathogenesis– a sequence of events in the response the cells and tissues to the etiologic agent, from the initial stimulus to the ultimate expression of the disease
Autopsy=Necropsy=Postmortem examination
Biopsy (incisional- only a sample is removed, excisional- entire component removed, pinch- biopsy forceps used and needle aspiration)
Cell Injury
Cellular Injury occurs when stress exceeds the cell’s ability to adapt. Risk of injury depends on:
➢ stress
➢ severity (e.g. slowly cutting blood supply – like atherosclerosis of renal artery cause atrophy vs fast – thrombus embolize renal artery resulting in infarction)
➢ type of cell (e.g. neurons susceptible to hypoxia within 3-5 mins).
Common causes of injury:
- Inflammation (e.g. autoimmune diseases)
- Nutritional deficiency or excess
- Hypoxia (e.g. MI, Stroke)
- Low oxygen delivery to tissue-
Tissue dependent on oxygen because it is the final acceptor of electrons in the ETC (oxidative phosphorylation). Low ETC efficiency = Lower ATP = Cellular injury.
Hypoxemia- Low partial pressure of O2 in the blood (PartO2 60mmHg, SaO290%. Caused by high altitude, hypoventilation, COPD, interstitial fibrosis of the lung. The decreased O2 carrying capacity of blood Usually arises with Hb loss or dysfunction
Ischemia/Reperfusion injury-paradoxically exacerbated cell injury after blood flow is restored. It contributes to tissue damage during myocardial and cerebral infarction and following therapies to restore blood flow
- Trauma (e.g. GSW)
- Genetic mutations
Other causes include Physical agents, Chemical agents and drugs, Infectious agents, and Immunological reactions.
Mechanisms of Cell Injury:
1. ATP depletion -Low levels of ATP result in loss of energy-dependent cellular functions impairing metabolism and normal homeostasis. Hypoxia, Ischemia and hypoxemia are manifestations due to O2 deficiency which causes cell injury by reducing aerobic oxidative respiration
2. Mitochondrial damage – Mitochondrial damage/dysfunction can cause:
➢ loss of electron transport chain located in the inner mitochondrial membrane causing a decrease in ATP.
➢ Cytochrome C present within mitochondria leak into the cytosol and activate apoptosis.
3. Ca influx – the influx of Ca2 cause activation of degradative enzymes. (ATPase, Phospholipase, Protease, Endonuclease)
4. Oxygen-derived free radicals – disruption of plasma membrane and organelles, loss of enzymatic activity and abnormal protein folding, mutations and DNA abnormalities.
• induced by radiant energy, drug metabolism, transition metals, NO
Free radical action can be decreased by antioxidants, transition metal-binding proteins and enzymes
5. Membrane damage – Breakdown of the plasma membrane can cause:
➢ cytosolic enzymes to leak into the serum. e.g., troponin- an indicator of MI.
6. Damage to DNA and proteins – Nuclear degradation: pyknosis (nuclear condensation) cause karyorrhexis (nuclear fragmentation caused by endonuclease-mediated cleavage) leading to karyolysis (nuclear dissolution).
Reversible Cell Injury-
Hallmark is cellular swelling. The decrease in ATP causes a decrease in the activity of Ca2+ and Na+/K+ pumps resulting in cellular swelling due to Na+ accumulating and pulling water into the cell. (earliest morphologic manifestation). May cause mitochondrial swelling.
- Loss of microvilli due to swelling.
- Plasma membrane changes (e.g., blebbing).
- ER swelling leads to ribosomal, polysomal detachment causing decreased protein synthesis.
- Nuclear changes (e.g., chromatin clumping).
- Rapid loss of function (e.g., myocardial cells are noncontractile after 1-2 minutes of ischemia).
- eosinophilia (due to decreased cytoplasmic RNA) and fatty change
Irreversible Cell Injury-
Hallmark is membrane damage. Leads to cell death.
Breakdown of plasma membrane cause:
➢ cytosolic enzymes to leak into the serum. e.g., troponin- an indicator of MI.
➢ the influx of Ca2 cause activation of degradative enzymes.
Mitochondrial damage/dysfunction causes:
➢ loss of electron transport chain located in the inner mitochondrial membrane causing a decrease in ATP.
➢ Cytochrome C present within mitochondria leak into the cytosol and activate apoptosis.
Rupture of the lysosomal membrane leads autolysis.
Nuclear degradation: pyknosis (nuclear condensation) cause karyorrhexis (nuclear fragmentation caused by endonuclease-mediated cleavage) leading to karyolysis (nuclear dissolution).
Cell Death
Morphologic hallmark of cell death is the loss of the nucleus.
Occurs via: pyknosis (nuclear condensation – nucleus shrinks down) followed by karyorrhexis (fragmentation – nucleus breaks up into pieces) karyolysis (dissolution – pieces are broken down to basic building blocks.)
2 mechanisms of Cell Death: Necrosis and Apoptosis
Morphologic alterations between the 2-
Necrosis: increased eosinophilia; nuclear shrinkage, fragmentation, and dissolution; the breakdown of the plasma membrane and organellar membranes; myelin figures; leakage and enzymatic digestion of cellular contents
Apoptosis: nuclear chromatin condensation; formation of apoptotic bodies (fragments of nuclei and cytoplasm)
Most common forms of Cellular Injury
- Ischemic and Hypoxic Injury (Mentioned above)
- Free Radical and ROS
- Chemical (Toxic) Injury – from direct binding or metabolite products of chemicals
certain agents and stresses induce distinctive alterations involving only subcellular organelles
These responses occur in Acute Lethal Injury, Chronic forms of Cell Injury and Adaptive Responses
Sub-Cellular Responses to Injury–
- Autophagy – in nutrient-deprived cells
- Hypertrophy of SER – when toxins are metabolized in SER, hypertrophy occurs as a compensatory mechanism to maximize removal
- Mitochondrial alterations – change in number, size, and shape of mitochondria
- Cytoskeletal alterations – the assembly and functions of cytoskeletal filaments
Cellular Edemas are small or large vacuoles that appear in the cytoplasm that can cause infections, introduce toxins, hypoxia, hypoproteinemia…etc. They are often seen in the Skin, Liver and Kidneys.
Necrosis and Apoptosis
For all cells, there are 2 basic mechanisms by which they bid their farewells, either they kill themselves or they are killed by an external injurious agent
Necrosis– (Necros=Dead)
Death of a large group of cells followed by acute inflammation, due to irreversible cell damage. Always due to pathologic processes except for necroptosis which is programmed necrosis in response to TNF alpha.
Result of 2 concurrent processes,
Protein Denaturation (coagulation) and Enzymatic Degradation of Cells (liquefaction)
Factors Causing Necrosis include Physical, Chemical and Biological
It can be caused by Ischemia, Trauma, Infection, Malignancy, Toxins, Inflammation…etc.
Types of Necrosis:
- Coagulative necrosis- Necrotic tissue remains firm, cell shape, organ structures are preserved by cellular proteins, but nucleus disappears. Usually, cytoplasm looks pink/red. Characteristic of ischemic infraction of any organ except the brain. Usually, the area of infarcted tissue is wedge-shaped and pale (wedge points to occlusion).
- Red, Hemorrhagic infarction occurs when blood re-enters a loosely organized tissue (i.e. 1. venous occlusion of tissues with multiple blood supplies- lungs, liver, intestine, testes) and 2. with reperfusion (say angioplasty), and forms free radicals, giving it a red colour.
- Pale, Anemic infarction occurs in solid organs with a single (end- arterial) blood supply like the heart, spleen, and kidneys.
- Liquefactive necrosis- Necrotic tissue becomes liquefied. Enzymatic lysis of cells and proteins result in liquefaction. Tissue structure is not preserved. Seen in –
➢ Brain infarction: microglial cells in brain hydrolyze tissue after death thus liquefied. Cystic spaces and cavitation may be seen.
➢ Abscess: walled-off area of dead tissue which is destroyed by Neutrophil enzymes.
➢ Pancreatitis: activation of pancreatic enzymes within the pancreas itself and digests itself.
- Gangrenous necrosis- coagulative necrosis resembling mummified tissue (dry gangrene). Characteristic of ischemia of lower limb (occlusion of popliteal a. in diabetes) and GI tract. If superimposed infection occurs, liquefactive necrosis occurs (wet gangrene).
- Caseous necrosis- soft, friable necrotic tissue with “cottage cheese-like” appearance. Combination of coagulative and liquefactive necrosis. Characteristic of granulomatous inflammation due to TB or fungal infection. Also seen with Nocardia infection.
- Fat necrosis- Necrotic adipose tissue with chalky-white appearance due to deposition of calcium. FA combine with Calcium and saponification gives white colour morphologically, dark blue histologically in H&E Classically seen in
➢ Trauma to fat (e.g., breast- can present as a mass; the presence of Ca)- Nonenzymatic, traumatic.
➢ Acute Pancreatitis- mediated damage of peripancreatic fat- Enzymatic.
- Fibrinoid necrosis- Necrotic damage to blood vessel wall causing of leaking of protein into the vessel wall (immune complexes combine with fibrin leading to vessel damage: Type III hypersensitive reaction.), resulting in bright pink staining. Characteristic of malignant hypertension (high BP, headache, renal failure) and vasculitis. *Preeclampsia usually in the third trimester (elevated BP and proteinuria) and may present with fibrinoid necrosis of the placenta.