Lecture 1 Flashcards by Da Vida (2024)

The study of disease (suffering)’Pathos- suffering
Logy-studying

The bridge between the basic sciences and clinical medicine
•The scientific foundation for all of medicine
•Made up of four disciplines ; anatomic pathology, microbiology, hematology and clinical chemistry or chemical pathology

Bridging discipline involving both basic science and clinical practice
•Devoted to the study of the structural and functional changes in cells, tissues, and organs that underlie disease.
•Achieved by the use of molecular, microbiologic, immunologic, chemical and morphologic techniques.

You’re finding out what happened to the suffering cells from the time they were normal to the time they started suffering till now that the person is exhibiting symptoms

Concerned with the basic reactions of cells and tissues to abnormal stimuli that underlie all diseases.

Concerned with the basic reactions of cells and tissues to abnormal stimuli that underlie all diseases.

Pathology ( anatomic pathology, microbiology, clinical chemistry and hematology)
•Autopsy ( anatomic pathology led the way)
•Microscopy ( histopathology) is modern

What happened during haruspicy
•Later discipline was fragmented
True or false

Haruspicy- 4th century BC in Babylonia rabbis examined slaughtered animals for evidence of disease

•Talmudic law “Thou shalt not eat anything that dyeth of itself,”
Haruspicy is an ancient practice of divination that involves examining the entrails of sacrificed animals, especially the liver, to predict future events or interpret the will of the gods. This method of divination was particularly prominent among the Etruscans and Romans.

To see for ones’ self
•The ‘thing’ that caused the death of an individual
•‘Thing’ may be supernatural, microbial, environmental, genetic…..
•We want to see what caused death !!!

Aristotle (384-322 BC) inspired the study of animal anatomy and development

•Ptolemy of Macedonia (367-282 BC) created the environment in which pathologic anatomy first flourished at The Alexandria Library

The first known dissection in Japan was in 456 AD when an autopsy done on the body of Princess Takukete following her suicide revealed fluid in the abdomen with a “stone.”

In China, human dissections were performed occasionally during the Sung dynasty.

Around 1250, there appeared a handbook, His Yuan Lu (Washing Away of Wrongs),
•This text described simple autopsy techniques and guidelines,
•It was the first recorded text dealing with forensic issues

•In 1045 AD, over a 2-day period, dissections of the bodies of 56 members of a band of rebels were recorded in an atlas.

AUTOPSY PRACTICE- EUROPE
•A Muslim from Tunisia ( Ifriqiya)
•Constantine the African (1020-1087), who had traveled widely arrived in Europe introducing the art of examining bodies

•He translated many works from Arabic to Latin

Confirmed Western physicians in their belief that medicine should be studied as a ‘rational system with close ties to philosophy, grounded in logical order and susceptible to methodical investigation’

Modern concept; two major classes of etiologic factors: intrinsic or genetic, and environmental / acquired (e.g., infectious, nutritional, chemical, physical).

Two Factors work hand in hand.
The Genetic and environmental factors. Either one of both of them happening.

Example: people are genetically predisposed to getting diabetes but if they control their sugar intake,they are less likely to get diabetes.
If you take in a lot of sugar,you will get the diabetes.

If someone isn’t genetically prone to diabetes and person consistently consumes large amounts of sugar,the person will get diabetes

The concept of one etiologic agent for one disease is no longer sufficient because genetic and environmental factors work hand in hand.
•Knowledge or discovery of the primary cause remains the backbone on which a diagnosis can be made, a disease understood, or a treatment developed.

Kochs postulate for microbiology:
-one bacteria causes one diseases
-that one bacteria should be the cause of every manifestation of the disease
-the bacteria should be isolated from the body and grown on culture or media
-the bacteria should be able to be inoculated back into the body to cause the same disease

One agent for one disease as Koch said isn’t sufficient because Two Factors work hand in hand.

Pathogenesis refers to the sequence of events in the response of cells or tissues to the etiologic agent, from the initial stimulus to the ultimate expression of the disease

•Morphologic changes refer to the structural alterations in cells or tissues that are either characteristic of the disease or diagnostic of the etiologic process

functional derangements and clinical manifestations
•The nature of the morphologic changes and their distribution in different organs or tissues influence normal function and determine the clinical features (symptoms and signs), course, and prognosis of the disease.

•Virtually all forms of organ injury start with molecular or structural alterations in cells

functional derangements and clinical manifestations
•The nature of the morphologic changes and their distribution in different organs or tissues influence normal function and determine the clinical features (symptoms and signs), course, and prognosis of the disease.

•Virtually all forms of organ injury start with molecular or structural alterations in cells

normal cell confined to a fairly narrow range of function and structure by its genetic programs of metabolism, differentiation, and specialization; by constraints of neighboring cells; and by the availability of metabolic substrates.

•Cells able to handle normal physiologic demands, maintaining a steady state called homeostasis(Hemostasis is the physiological process that stops bleeding at the site of an injury while maintaining normal blood flow elsewhere in the circulation)

Body response to stress

Severe physiologic stresses and some pathologic stimuli may bring about a number of physiologic and morphologic cellular adaptations, during which new but altered steady states are achieved, preserving the viability of the cell and modulating its function as it responds to such stimuli

So for a normal cell, homeostasis is going on well. When there is stress, the cell tries to adapt to it. If it can’t adapt, it leads to cell injury. This injury could be reversible or irreversible. If the injury is (mild,transient), it is reversible. If it is severe and progressive, it becomes irreversible.
If reversible, it’ll go back to the normal way the cell was.
If irreversible, it’ll undergo either necrosis or apoptosis.

If the cell went through an injury or injurious stimulus but not a stress, the cell becomes injured. If the injury is mild,transient it is reversible. If it is severe and progressive, it becomes irreversible.
If reversible, it’ll go back to the normal way the cell was.
If irreversible, it’ll undergo either necrosis or apoptosis

So for stresss, the body adapts or the cell adapts but for a cellular injury, it moves into being reversible or irreversible.
If it can’t adapt, it now becomes a cellular injury and then depending on the kind of injury, it is either reversible or irreversible

Refers to an increase in the size of cells, resulting in an increase in the size of the organ.
•The hypertrophied organ has no new cells, just larger cells. The increased size of the cells is due not to cellular swelling but to the synthesis of more structural components. This is due to Structural proteins increase in cells causing increased cell size and consequently hypertophy.

•Occurs in nondividing cells (e.g., myocardial fibers)
•May be pathological or physiological

Physiologic (example: increased uterus size during pregnancy) and pathological hypertrophy(example: left ventricular hypertrophy. Hypertrophy of left ventricle due to increased workload on the heart)

Physiologic hyperplasia
•Grouped into;
1.Hormonal hyperplasia e.g. pregnancy changes in the uterus and breasts
2.Compensatory hyperplasia e.g. regeneration of the liver after partial hepatectomy

Mechanism; increased local production of growth factors, increased levels of growth factor receptors on the responding cells, or activation of particular intracellular signaling pathways

Pathologic hyperplasia
•Pathologic hyperplasia; constitutes a fertile soil in which cancerous proliferation may eventually arise, e.g. patients with hyperplasia of the endometrium are at increased risk for developing endometrial cancer

Pathological Hypertrophy of heart muscle mechanism:
Anytime there is a mechanical stretch of the heart muscle.
Hypertension increases the stretch on the heart muscles increasing EDV.
Left ventricle pumps blood to the entire body and is able to do that due to the elasticity of the heart muscles and the volume of blood that comes in.
CO=SVxHR
MAP=COxTPR

The mechanical stretch on the heart muscles causes signals to be sent to the cardiomyoctes which activates alpha adrenergic agonists and the hormones and receptors for growth factors such as insulin like growth factor 1.
This causes signal transduction.
Transcription factors are produced to:
- [ ] Induction of fetal genes: not used to level of work adult cardiac cells do. So there’s increased sketching and decreased something so it can contain the amount of work
- [ ] Increased synthesis of contractile proteins
- [ ] Increased production of growth factors

The above three factors contribute to the increase in the size of the cardiomyocytes.

A reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.
•It may represent an adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment.
•The influences that predispose to metaplasia, if persistent, may induce malignant transformation in metaplastic epithelium..

Metaplasia: uncontrollable increase in number of cells. The cell look like the normal cell morphology.
When it moves into the blood vessels or crosses basem*nt membrane into the connective tissues and surrounding areas that’s when you say the cancer has metastized

Cells have the normal morphology in metaplasia while cells have a different morphology in dysplasia. Dysplasia: uncontrollable increase in number of cells with a change in structure of normal cells or differences in the normal structure of the cells

Shrinkage in the size of the cell by loss of cell substance.
•When a sufficient number of cells are involved, the entire tissue or organ diminishes in size, or becomes atrophic.
•Can be physiologic or pathological. Physiologic example is aging(organs and tissues decrease in size as aging occurs. This is called senile atrophy. It involves loss of muscle mass). Another example is the return of the uterus to the normal size after giving birth(involution)

Pathological:
Disuse atrophy, reduced blood flow to the area cause reduced usage,etc

That’s correct! Muscle atrophy, also known as muscle wasting, occurs when there is a loss of contractile proteins, leading to a reduction in muscle size and strength.

In atrophy, the following changes occur:

1. Loss of contractile proteins: Actin and myosin filaments are broken down, leading to a decrease in muscle fiber size and number.
2. Reduced muscle protein synthesis: The rate at which new muscle proteins are built decreases, contributing to muscle loss.
3. Increased muscle protein degradation: Muscle proteins are broken down more quickly, leading to a net loss of muscle tissue.
4. Disruption of muscle fiber structure: The organization and alignment of muscle fibers are disrupted, leading to a loss of muscle function.

As a result, the muscle reduces in size, and its strength and function are impaired. Atrophy can occur in various contexts, such as:

• Disuse (e.g., immobilization or prolonged bed rest)
• Aging (sarcopenia)
• Malnutrition or inadequate protein intake
• Certain diseases (e.g., muscular dystrophy, cancer cachexia)
• Hormonal imbalances (e.g., testosterone deficiency)

In atrophy, the structural proteins (like collagen and elastin) may also be affected, leading to changes in muscle tissue architecture and function.

Great question! Let me know if you’d like more details on muscle atrophy or related topics!

Decreased workload (atrophy of disuse)
• Loss of innervation (denervation atrophy).
• Diminished blood supply.
•Inadequate nutrition
•Loss of endocrine stimulation.
•Aging (senile atrophy).
•Pressure.

How diminished blood supply causes atrophy:
- [ ] By causing Tissue hypoxia leading to reduced oxygen in cells that is used for their cellular function leading to shrinking of the cells
- [ ] It can also cause decreased workload cuz reduced blood supply to a certain part makes it difficult to use that part of the body

So when the cell loses its function or is unable to perform its function, it leads to atrophy.

Thymus gland is almost vanished due to atrophy in aging people

Pressure as a cause of atrophy:
Excessive use of something can make it diminish In size

Reversible injury; the hallmarks of reversible injury are reduced oxidative phosphorylation(this is the process by which mitochondria produces ATP), adenosine triphosphate (ATP) depletion, and cellular swelling caused by changes in ion concentrations and water influx. In addition: ATP DEPLETION, Impaired mitochondrial function
4. Increased ROS production
5. Disrupted electron transport chain

Further understanding:
So oxidative phosphorylation will be reduced because there is reduced ADP generation. ADP is the substrate for ATP synthase. ATP synthase uses ADP and inorganic phosphate to produce ATP. With less ADP available, the enzyme has less substrate to work with, reducing the rate of ATP synthesis and reducing oxidative phosphorylation
Reversible cell injury refers to cellular damage that can be reversed if the harmful stimulus is removed. The hallmarks of reversible cell injury primarily reflect early cellular responses to stress or injury
The key features include:

1. Cellular Swelling: Due to the failure of ion pumps in the plasma membrane, especially the Na+/K+ ATPase pump, leading to an influx of sodium and water into the cell.
2. Fatty Change (Steatosis): Accumulation of lipid droplets within the cytoplasm, often seen in organs involved in lipid metabolism, like the liver.
3. Membrane Blebbing: Formation of protrusions or blebs in the plasma membrane due to cytoskeletal disruption.
4. Mitochondrial Swelling: Swelling and distortion of mitochondria, which may lead to decreased ATP production but are not yet irreversibly damaged.
5. Dilation of the Endoplasmic Reticulum: Expansion of the ER, leading to detachment of ribosomes and disruption of protein synthesis.
6. Detachment of Ribosomes from the Rough ER: Leading to impaired protein synthesis.
7. Chromatin Clumping: Aggregation of nuclear chromatin due to changes in ionic balance, especially pH.
8. Cellular and Organelle Disorganization: Initial reversible changes in the structure and function of various organelles within the cell.
9. Increased Plasma Membrane Permeability: Leading to an imbalance of ions and water across the membrane, contributing to cellular swelling.
10. Accumulation of Intracellular Ions: Particularly calcium, which can activate various enzymatic pathways that can lead to further cell damage if not controlled.

These changes are generally reversible if the injurious stimulus is removed and the cell can restore homeostasis.

Irreversible injury; structural changes (e.g., amorphous densities in mitochondria, indicative of severe mitochondrial damage) and functional changes (e.g., loss of membrane permeability) are indicative of cells that have suffered irreversible injury.

Irreversible cell injury refers to a state where cell damage has progressed to a point beyond recovery, ultimately leading to cell death. Several hallmark features characterize this irreversible injury, distinguishing it from reversible damage. These hallmarks include:

• Irreversible Mitochondrial Dysfunction: Mitochondria lose their ability to produce ATP. Significant mitochondrial damage includes the loss of membrane potential and the formation of mitochondrial permeability transition pores, leading to the release of pro-apoptotic factors.

• Plasma Membrane Disruption: Loss of membrane integrity leads to an uncontrolled influx of calcium and other ions, as well as leakage of cellular contents into the extracellular space.
• Lysosomal Membrane Damage: Release of lysosomal enzymes into the cytoplasm, causing enzymatic digestion of cellular components.

• Pyknosis: Nuclear shrinkage and increased basophilia due to chromatin condensation.
• Karyorrhexis: Fragmentation of the nucleus into smaller pieces.
• Karyolysis: Dissolution of the nuclear structure, resulting in a loss of chromatin staining.

• Increased Eosinophilia: The cytoplasm appears more pink when stained with hematoxylin and eosin (H&E) due to the denaturation of proteins and loss of RNA.
• Cytoplasmic Vacuolization: Formation of large vacuoles within the cytoplasm as a result of autophagy and other degradative processes.

• Leakage of Intracellular Enzymes: Enzymes and proteins, such as lactate dehydrogenase (LDH) and creatine kinase (CK), are released into the extracellular space and bloodstream, serving as markers of cell death and tissue damage.

• Functional Impairment: Complete loss of specific cellular functions, such as contraction in muscle cells or electrical activity in neurons

When I mentioned “increased basophilia” in the context of pyknosis, I was referring to the fact that the condensed chromatin in the nucleus becomes more intensely stained with basic dyes.

Basophilia is a term used to describe the ability of a substance to attract basic dyes, such as hematoxylin and eosin (H&E). In the context of histology and cytology, basophilia is often used to describe the staining properties of cellular structures.

In the case of pyknosis, the condensed chromatin becomes more basophilic because the DNA and associated proteins are packed more tightly together. This increased density of negatively charged molecules (such as phosphate groups in DNA) creates a stronger attraction for positively charged basic dyes.

As a result, the pyknotic nucleus appears more intensely stained with basic dyes, often appearing dark blue or purple under a microscope. This is in contrast to the surrounding cytoplasm, which may appear more pale or eosinophilic (staining with acidic dyes).

So, to summarize:

• Basophilia refers to the ability of a substance to attract basic dyes.
• In pyknosis, the condensed chromatin becomes more basophilic due to the increased density of negatively charged molecules.
• This results in the pyknotic nucleus appearing more intensely stained with basic dyes under a microscope.

Irreversible cell injury: Loss of membrane permeability means the cell isn’t able to control what goes in and out of it. There is lysosome rupture. Lysosomes contain certain chemicals that destroy the cell

One of the reasons reversible cell injury is reversible is cuz the damage isn’t as bad and lysosomes don’t rupture

Diff between reversible and irreversible cell injury

Important targets of injurious stimuli
1.Aerobic respiration involving mitochondrial oxidative phosphorylation and production of ATP
2.The integrity of cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends(attack to this area by injurious stimuli leads to high sodium in cells due to failure of Sodium potassium pumps leading to swelling of cells)
3.Protein synthesis-components in cell are held together by proteins. Example is the cytoskeleton. Problem in protein synthesis can cause deranged enzymes such as derangement in enzymes in glycolytic pathway (example streptokinase) so the cell isn’t able to produce the mediators for ATP synthesis
4.The cytoskeleton
5.The integrity of the genetic apparatus of the cell.(Example is radiation causing injury to DNA which will affect integrity of genetic apparatus

Summary:
Injury to membrane or cell affects these key areas or causes:
1.Mitochondrial damage leads to reduced ATP production and then loss of energy dependent cellular functions like sodium potassium atpase pumps.
2.Injury to lysosomes causing enzymatic digestion of cellular components
3. Injury to plasma membrane causing loss of integrity of plasma membrane leading to loss of cellular contents
4. Increased intracellular calcium leading to protein breakdown and dna damage
5. Release or ROS such as nitric oxide,hydrogen peroxide,hydrochloride also leading to protein breakdown and dna damage

Decreased ATP synthesis and depletion are frequently associated with both hypoxic and chemical (toxic) injury

• ATP depletion to <5-10% of normal levels result in;
1.Reduction in the activity of the plasma membrane energy-dependent sodium pump (ouabain-sensitive Na+,K+-ATPase) which leads to increased sodium,water and calcium influx and increased potassium efflux causing ER swelling and the whole cell to swell up
2.Altered cellular energy metabolism-reduced ATP means now the cell has to undergo anaerobic glycolysis instead of aerobic. More of the ATP or high amounts of it is produced from aerobic glycolysis in the cristae of the mitochondria. This anaerobic glycolysis leads to reduced glycogen,reduced ph and then clumping of nuclear chromatin
3.Failure of the Ca2+ pump leads to influx of Ca2+, with damaging effects on numerous cellular components
4.Structural disruption of the protein synthetic apparatus, manifested as detachment of ribosomes from the rough endoplasmic reticulum and dissociation of polysomes into monosomes, with a consequent reduction in protein synthesis and increased lipid deposition
5.Unfolded protein response is triggered

cristae **: The folds of the inner mitochondrial membrane where the electron transport chain and ATP synthesis take place.
- Matrix: The innermost part of the mitochondrion where the Krebs cycle occurs.

Increases of cytosolic Ca2+
•Oxidative stress
•Breakdown of phospholipids
•Lipid breakdown products

Damage RESULTS IN;
1.Formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial permeability transition pore

1. Mitochondrial Permeability Transition (MPT) pore formation: A high-conductance channel forms in the mitochondrial membrane, allowing solutes and water to flow into the mitochondria, leading to:
   
   • Mitochondrial swelling
   • Mitochondrial dysfunction
   • Release of pro-apoptotic factors

2.Sequestration between the outer and inner membranes of the mitochondria of several proteins that are capable of activating apoptotic pathways( cytochrome c and proteins that indirectly activate apoptosis inducing enzymes called caspases). The statement you’ve provided refers to a critical step in the intrinsic (mitochondrial) pathway of apoptosis, where certain proteins sequestered between the outer and inner membranes of the mitochondria are released to initiate the apoptotic process. Here’s a breakdown:

1. Sequestration of Proteins:
   
   • Under normal conditions, proteins like cytochrome c and others that can promote apoptosis are sequestered in the intermembrane space of the mitochondria (the space between the outer and inner mitochondrial membranes).
2. Release of Cytochrome c:
   
   • In response to apoptotic stimuli (e.g., DNA damage, oxidative stress), the mitochondrial outer membrane becomes permeable.
   • This permeability allows cytochrome c and other pro-apoptotic proteins to be released into the cytoplasm.
3. Activation of Caspases:
   
   • Once in the cytoplasm, cytochrome c interacts with a protein called Apaf-1 (Apoptotic protease activating factor-1) to form a complex known as the apoptosome.
   • The apoptosome then recruits and activates procaspase-9, which is cleaved to form active caspase-9.
   • Caspase-9 subsequently activates other caspases (like caspase-3), which are responsible for executing the cell death program by degrading cellular components.
4. Apoptotic Pathway:
   
   • The release of cytochrome c is a key event in the intrinsic apoptotic pathway.
   • This pathway is tightly regulated and ensures that cells undergo controlled, programmed cell death in response to internal stress signals.

• Cytochrome c: A protein normally involved in the electron transport chain, but also crucial for the activation of the intrinsic apoptotic pathway when released into the cytoplasm.
• Caspases: A family of protease enzymes that play essential roles in programmed cell death (apoptosis). They are activated in a cascade, leading to the systematic dismantling of the cell.

• Sequestration of apoptotic proteins like cytochrome c within the mitochondria keeps the apoptotic machinery in check.
• Release of these proteins into the cytoplasm triggers the activation of caspases, leading to apoptosis.

This process ensures that cells can be efficiently and systematically eliminated when they are damaged or no longer needed, preventing potential harm to the organism.

Sequestration of pro-apoptotic proteins*: Between the outer and inner mitochondrial membranes, several proteins are sequestered, including:
- Cytochrome c: A key electron transport chain protein that can activate caspases and induce apoptosis
- Pro-apoptotic Bcl-2 family members: Proteins like Bax, Bak, and Bid, which can activate caspases and induce apoptosis

These sequestered proteins can then be released into the cytosol, triggering apoptotic pathways and ultimately leading to programmed cell death (apoptosis).
S several key factors responsible for triggering apoptotic pathways are located in the mitochondria. These factors include:

1. Cytochrome c: A protein that’s normally involved in the electron transport chain, but when released into the cytosol, it activates caspases and triggers apoptosis.
2. Smac/DIABLO: A protein that inhibits the activity of IAPs (inhibitors of apoptosis proteins), allowing caspases to activate and drive apoptosis.
3. Omi/HtrA2: A serine protease that can activate caspases and trigger apoptosis.
4. Bcl-2 family members: A family of proteins that regulate apoptosis by either promoting (pro-apoptotic) or inhibiting (anti-apoptotic) mitochondrial outer membrane permeabilization (MOMP).

These mitochondrial factors are normally sequestered within the mitochondria, but when the mitochondria are damaged or dysfunctional, they can be released into the cytosol, triggering apoptotic pathways
Sequestration of proteins refers to the process by which proteins are selectively bound or trapped by other molecules, such as lipids, nucleic acids, or other proteins, and removed from their normal cellular environment or activityh

The MPT pore formation and protein sequestration are critical steps in the mitochondrial pathway of apoptosis, which is a key mechanism of cell death in response to cellular stress, injury, or damage.

CAUSES OF DEFECTS IN MEMBRANE PERMEABILITY
•Mitochondrial dysfunction-losss of sodium potassium atpase causing cell membrane to swell up
•Loss of membrane phospholipids
•Cytoskeletal abnormalities.
•Reactive oxygen species.
•Lipid breakdown products.

Here are some ways in which lipid breakdown products can disrupt membrane permeability:

1. Lysophospholipids: These products of phospholipid breakdown can insert into the mitochondrial membrane, causing it to become more permeable.
2. Fatty acid derivatives: Certain fatty acid derivatives, such as palmitate, can alter the fluidity and permeability of the mitochondrial membrane.
3. Oxidized lipids: Oxidized lipids, such as oxidized cholesterol, can disrupt the mitochondrial membrane structure and function, leading to increased permeability.
4. Ceramide: This sphingolipid breakdown product can form channels in the mitochondrial membrane, leading to increased permeability

Two phenomena consistently characterize irreversibility;
1.The inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) or when Mitochondria is destroyed

2.Profound disturbances in membrane function.-Membrane of cell is destroyed

State two light microscopic changes in the cell that are seen in reversible cell injury

State four ultra structural changes seen in reversible injury

Two light microscopic changes are recognizable;
1.Cellular swelling and bleb formation
2.Fatty change and fatty deposits especially in the hepatocytes

Ultrastructural changes in reversible injury include:
1.Plasma membrane alterations
2.Mitochondrial changes
3.Dilation of the endoplasmic reticulum-this displaces the ribosomes on it
4.Nuclear alterations

Spectrum of morphologic changes that follow cell death in living tissue
•Morphologic appearance of necrosis is the result of denaturation of intracellular proteins and enzymatic digestion of the cell. Necrotic cells often exhibit:

• Cytoplasmic swelling
• Nuclear pyknosis (condensation)
• Karyolysis (nuclear breakdown)
• Cell lysis (rupture)

As the cell dies, its components are broken down and removed by the body’s clearance mechanisms. In some cases, dead cells may be replaced by myelin figures, which are composed of lipid material and can be seen in conditions such as infarction (tissue death due to lack of blood supply)
•Dead cells may be replaced by myelin figures. Dead cells may be replaced by myelin figures, which are formed by the breakdown of cellular membranes and the accumulation of lipid material.

Morphologic variants of necrosis
•Coagulative necrosis; implies preservation of the basic outline of the coagulated cell for a span of at least some days.example is the heart muscle which undergoes coagulative necrosis

Coagulative Necrosis and Liquefactive Necrosis are two distinct types of tissue necrosis that can result from different infections.

Characteristics:
- Coagulative necrosis is characterized by the preservation of the basic outline of the coagulated cell for a few days. The architecture of dead tissues is preserved for at least some days.
- It typically occurs due to ischemia or infarction, where blood supply is cut off, leading to tissue death.

Infections Causing Coagulative Necrosis:
- Bacterial Infections:
- Clostridium perfringens: Causes gas gangrene, leading to coagulative necrosis in the muscles.
- Bacillus anthracis: Causes anthrax, which can result in black eschar with coagulative necrosis in cutaneous anthrax.
- Certain bacterial infections (e.g., anthrax, clostridial infections) can cause coagulative necrosis through vascular damage, thrombosis, and ischemia
- Viral Infections:
- While viral infections more commonly cause liquefactive necrosis in certain tissues, some can indirectly lead to ischemia and subsequent coagulative necrosis (e.g., by causing vascular damage and thromboembolism).

You’re looking for the common viral infections that lead to ischemia. Here are some of the most common ones:

1. Herpesviruses (HSV, VZV)
2. Cytomegalovirus (CMV)
3. Influenza
4. HIV
5. Respiratory syncytial virus (RSV)

These viruses can cause ischemia through various mechanisms, including vasculitis, endothelial dysfunction, and thrombosis.

•Liquefactive necrosis is characteristic of focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of inflammatory cells.

Focal bacteria refer to bacteria that are localized to a specific area or focus within a tissue or organ. In other words, they are concentrated in a particular region, rather than being widely distributed throughout the body.

Focal bacteria can cause a range of effects, including:

1. Local inflammation: The immune response to the bacteria can lead to inflammation in the surrounding tissue.
2. Tissue damage: The bacteria can produce toxins or enzymes that damage the surrounding tissue.
3. Abscess formation: The bacteria can cause the formation of an abscess, a pocket of pus and debris.
4. Granuloma formation: The immune response to the bacteria can lead to the formation of a granuloma, a type of inflammatory nodule.

Examples of focal bacteria include:

1. Staphylococcus aureus (can cause abscesses or granulomas)
2. Mycobacterium tuberculosis (can cause granulomas in the lungs)
3. Bartonella henselae (can cause focal lesions in the skin or lymph nodes)

Focal bacteria can be diagnosed through various methods, including:

1. Imaging studies (e.g., X-rays, CT scans)
2. Biopsy (examining a tissue sample under a microscope)
3. Microbiological cultures (growing the bacteria in a laboratory)

Treatment for focal bacteria typically involves antibiotics and, in some cases, surgical drainage or removal of the affected tissue.

Liquefaction completely digests the dead cells. Example is in brain infections

### Liquefactive Necrosis

Characteristics:
- Liquefactive necrosis results in the transformation of the tissue into a liquid viscous mass. It is often associated with the presence of abscesses and pus due to the action of hydrolytic enzymes.
- It is common in tissues with high enzymatic content, such as the brain, and in abscesses due to bacterial infections.
Examples of tissues with high enzymatic content include:

1. Pancreas: The pancreas contains digestive enzymes that can break down dead tissue, leading to liquefactive necrosis.
2. Liver: The liver contains enzymes that can break down dead tissue, leading to liquefactive necrosis.
3. Spleen: The spleen contains enzymes that can break down dead tissue, leading to liquefactive necrosis.
4. Lymph nodes: Lymph nodes contain enzymes that can break down dead tissue, leading to liquefactive necrosis.
5. Adipose tissue (fat tissue): Adipose tissue contains lipases, which can break down dead tissue, leading to liquefactive necrosis.

These tissues are more prone to liquefactive necrosis due to their high enzymatic content, which can facilitate the breakdown of dead cells and tissues.

On the other hand, tissues with low enzymatic content, such as muscle and bone, are more likely to undergo coagulative necrosis

Infections Causing Liquefactive Necrosis:
- Bacterial Infections:
- Staphylococcus aureus: Causes abscesses in various tissues leading to liquefactive necrosis.
- Streptococcus pyogenes: Can cause severe soft tissue infections, including necrotizing fasciitis, which involves liquefactive necrosis.
- Pseudomonas aeruginosa: Known for causing abscesses with liquefactive necrosis, especially in immunocompromised patients.

• Fungal Infections:
  
  • Aspergillus spp.: Can cause aspergillosis, leading to lung abscesses with liquefactive necrosis.
  • Candida spp.: Can lead to abscesses in various organs, often involving liquefactive necrosis.
• Viral Infections:
  
  • Herpes Simplex Virus (HSV): Can cause encephalitis, leading to liquefactive necrosis in the brain.
  • Cytomegalovirus (CMV): In immunocompromised patients, CMV infections can lead to extensive tissue necrosis, including liquefactive necrosis in organs like the lungs and the brain.

•Other terms include; gangrenous necrosis(due to occlusion of blood vessel proximal to the site of the necrosis) and wet gangrene-when inflammatory cells are involved

Fat necrosis
•Descriptive of areas of fat destruction, typically occurring as a result of release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity.
Fat necrosis is a type of necrosis that specifically affects fatty tissues. It’s characterized by the destruction of fat cells, leading to the release of fatty acids and other lipolytic products.

As you mentioned, fat necrosis often occurs as a result of:

1. Release of activated pancreatic lipases: These enzymes break down fat cells, leading to their destruction.
2. Pancreatic injury or inflammation: Conditions like pancreatitis can lead to the release of pancreatic lipases, causing fat necrosis.
3. Peritoneal cavity involvement: The peritoneum is a membrane lining the abdominal cavity. When it’s affected by inflammation or injury, it can lead to fat necrosis.

Fat necrosis can also occur in other situations, such as:

• Trauma or injury to fatty areas
• Infections like cellulitis or abscesses
• Cancer or radiation therapy
• Certain medications or drugs

•Histologically it takes the form of foci of shadowy outlines of necrotic fat cells, with basophilic calcium deposits, surrounded by an inflammatory reaction.

In ischemic tissues, anaerobic energy generation stops after glycolytic substrates are exhausted, or glycolytic function becomes inhibited by the accumulation of metabolites that would have been removed otherwise by blood flow
Ischemia injures tissues faster than hypoxia for several reasons:

1. Reduced substrate delivery: Ischemia reduces blood flow, which means that tissues not only receive less oxygen but also less glucose, amino acids, and other essential nutrients. This impairs cellular metabolism and energy production.
2. Accumulation of metabolic waste: With reduced blood flow, waste products like lactic acid, urea, and creatinine build up in tissues, leading to cellular toxicity and damage.
3. Increased inflammation: Ischemia triggers an inflammatory response, which can lead to tissue damage and exacerbate injury.
4. Disrupted cellular homeostasis: Ischemia disrupts the balance of ions, water, and electrolytes within cells, leading to cellular swelling, damage, and death.
5. Faster energy depletion: Ischemia depletes cellular energy stores (ATP) faster than hypoxia, as both oxygen and substrates are limited.
6. More severe acidosis: Ischemia leads to a more severe acidotic state (increased lactic acid and decreased pH), which damages cellular structures and functions.

In contrast, hypoxia alone (without ischemia) may still allow for some glucose and substrate delivery, enabling cells to maintain basic metabolic functions and survive for a longer period.

Keep in mind that both ischemia and hypoxia can cause tissue injury, but ischemia tends to be more severe and rapid due to the combination of reduced substrate delivery, metabolic waste accumulation, and disrupted cellular homeostasis.
•For this reason, ischemia tends to injure tissues faster than does hypoxia.

Here’s a clinical question based on our previous discussion:

Clinical Question:

A 40-year-old male patient presents with severe leg pain and numbness after a traumatic injury. His leg is pale, cool to the touch, and has a decreased pulse. Which type of injury is most likely to cause tissue damage faster, considering the patient’s presentation?

A) Hypoxic injury
B) Ischemic injury
C) Traumatic injury
D) Neurogenic injury

Answer:

B) Ischemic injury

Explanation:

The patient’s presentation suggests ischemia, which is characterized by reduced blood flow to the affected limb, leading to decreased oxygen and substrate delivery. This causes tissue damage faster than hypoxia alone, as ischemia impairs both oxygen and substrate delivery, leading to cellular energy depletion, metabolic waste accumulation, and disrupted cellular homeostasis. The patient’s symptoms, such as pale and cool skin, decreased pulse, and numbness, are consistent with ischemic injury.

Let me know if you have any further questions or if you’d like me to clarify anything!

CK and LDH

There is increased leakage of enzymes CK and LDH
There is also loss of phospholipid,cytoskeletal alterations,free radicals,lipid breakdown

Ischaemia-reperfusion injury
•New damaging processes are set in motion during reperfusion, causing the death of cells that might have recovered otherwise
Proposed mechanisms for this injury include:
1.Increased generation of oxygen free radicals from parenchymal and endothelial cells and from infiltrating leukocytes.
2.Mitochondrial permeability transition
3.Inflammation and activation of the complement pathway

During reperfusion, there is a sudden increase in oxygen delivery to the tissues, which can lead to an overproduction of reactive oxygen species (ROS). This occurs for several reasons:

1. Replenished oxygen: After a period of ischemia, the tissues are oxygen-depleted. When blood flow is restored, oxygen rushes in, and the sudden increase can lead to an overabundance of ROS.
2. Mitochondrial dysfunction: Ischemia can damage mitochondria, making them more prone to generating ROS during reperfusion.
3. Activation of enzymes: Reperfusion triggers the activation of enzymes like xanthine oxidase, NADPH oxidase, and cyclooxygenase, which can produce ROS as a byproduct.
4. Inflammation: Reperfusion initiates an inflammatory response, which leads to the production of ROS by immune cells like neutrophils and macrophages.
5. Disrupted cellular metabolism: Reperfusion can cause a sudden shift from anaerobic to aerobic metabolism, leading to an increase in ROS production.

The excessive ROS production during reperfusion can overwhelm the body’s natural antioxidant defenses, leading to oxidative stress, cellular damage, and tissue injury.

Does that help clarify things? Let me know if you have further questions!

Mitochondrial permeability transition*: Reperfusion can cause mitochondrial membranes to become permeable, leading to the release of pro-apoptotic factors and the disruption of cellular energy production.
3. Inflammation and complement activation: Reperfusion triggers an inflammatory response, activating the complement pathway and leading to the production of pro-inflammatory cytokines and chemokines.

A pathway of cell death that is induced by a tightly regulated intracellular program in which cells destined to die activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins.

Proapoptotic and anti-apoptotic genes regulate apoptosis. Pro-BAX
Anti-BCL2
•The cell’s plasma membrane remains intact, but its structure is altered in such a way that the apoptotic cell becomes an avid target for phagocytosis

The Bcl-2 family is a group of proteins that regulate apoptosis (programmed cell death) by controlling the mitochondrial pathway.

The Bcl-2 family members can be divided into two main subgroups:

1. Anti-apoptotic (pro-survival) members:
   
   • Bcl-2
   • Bcl-xL
   • Bcl-w
   • Mcl-1
2. Pro-apoptotic (pro-death) members:
   
   • Bax
   • Bak
   • Bad
   • Bid
   • Bim
   • Puma
   • Noxa

Bax, specifically, is a pro-apoptotic member of the Bcl-2 family. It can form hom*odimers or heterodimers with other Bcl-2 family members, leading to the formation of pores in the mitochondrial outer membrane, which ultimately triggers apoptosis.

The Bcl-2 family members interact with each other and with other proteins to regulate the mitochondrial pathway of apoptosis. The balance between pro-apoptotic and anti-apoptotic Bcl-2 family members determines the cellular fate: survival or death.

As an anti-apoptotic protein, Bcl-2 inhibits the activation of caspases, which are enzymes that carry out the process of apoptosis. By inhibiting caspases, Bcl-2 prevents cell death and promotes cell survival.

Cell death by this pathway does not elicit an inflammatory reaction in the host but necrosis does elicit inflammatory reactions.

Apoptotic bodies are formed and the immune system and macrophages and things recognize them and get involved and destroy the cell with the apoptotic bodies on them

•Responsible for numerous physiologic, adaptive, and pathologic events.

Apoptosis is important for Actively dividing cells with high turnover rates cuz some of the cells must definitely die physiologically for other cells to take their place and so if those older cells are not programmed to die, how will the new cells take their place?

Cell shrinkage. The cell is smaller in size(but is bigger in size in necrosis); the cytoplasm is dense; and the organelles, although relatively normal, are more tightly packed.
•Chromatin condensation. This is the most characteristic feature of apoptosis. (But in necrosis there is karyolysis,pyknosis and karyohexxis)
The chromatin aggregates peripherally, under the nuclear membrane, into dense masses of various shapes and sizes. The nucleus itself may break up, producing two or more fragments.
Plasma membrane is disrupted in necrosis but is maintained in apoptosis

Formation of cytoplasmic blebs and apoptotic bodies. The apoptotic cell first shows extensive surface blebbing, then undergoes fragmentation into membrane-bound apoptotic bodies composed of cytoplasm and tightly packed organelles, with or without nuclear fragments.

•Phagocytosis of apoptotic cells or cell bodies, usually by macrophages.

while both apoptosis and necrosis may exhibit chromatin condensation, the hallmark of apoptosis lies in the consistent and peripheral pattern of chromatin aggregation under the nuclear membrane, which is a critical histological feature used to distinguish it from necrosis.

Timing: Chromatin condensation in apoptosis is typically an early and consistent feature, occurring as part of the programmed cell death process.
•Pattern: In apoptosis, chromatin condensation is uniform and peripheral, whereas in necrosis, it may be irregular and accompanied by other nuclear changes depending on the type of necrosis.

Biochemical features of apoptosis
•Protein Cleavage; protein hydrolysis involving the activation of several members of a family of cysteine proteases named caspases.
•DNA Breakdown; by Ca2+- and Mg2+-dependent endonucleases.
•Phagocytic Recognition; apoptotic cells express phosphatidylserine in the outer layers of their plasma membranes. Thrombospondin, an adhesive glycoprotein, is also expressed on the surfaces of some apoptotic bodies

Apoptosis, also known as programmed cell death, is characterized by several biochemical features, including:

1. Protein Cleavage: Protein hydrolysis (cleavage of procaspases) leads to the activation of caspases.Procaspases are inactive precursors of caspases, and they require cleavage by other proteases or by autocatalytic processes to become active. This cleavage removes inhibitory domains and allows the caspase to adopt an active conformation.
2. DNA Breakdown: Ca2+- and Mg2+-dependent endonucleases fragment DNA into smaller pieces, resulting in a characteristic “ladder-like” pattern on gel electrophoresis.
3. Phagocytic Recognition: Apoptotic cells exhibit changes in their plasma membranes, including:
   
   • Externalization of phosphatidylserine (PS) from the inner leaflet to the outer leaflet, which serves as an “eat me” signal for phagocytic cells.
   • Expression of thrombospondin, an adhesive glycoprotein, on the surfaces of some apoptotic bodies, facilitating their recognition and clearance by phagocytes.

Additionally, other biochemical features of apoptosis include:

• Mitochondrial Outer Membrane Permeabilization (MOMP): Disruption of the mitochondrial outer membrane, leading to the release of cytochrome c and other pro-apoptotic factors.
• Caspase Cascade: Activation of initiator caspases (e.g., caspase-8, caspase-9) and executioner caspases (e.g., caspase-3, caspase-6, caspase-7), resulting in a cascade of proteolytic events.
• Cell Shrinkage: Reduction in cell volume due to the loss of water and ions.
• Membrane Blebbing: Formation of membrane-bound blebs, which can contain fragmented DNA and other cellular components.

These biochemical features contribute to the characteristic morphological changes associated with apoptosis, including cell shrinkage, nuclear condensation, and membrane blebbing.

Apoptosis is induced by a cascade of molecular events that may be initiated in distinct ways and culminate in the activation of caspases

•Divided into an initiation phase, during which caspases become catalytically active, and an execution phase, during which these enzymes act to cause cell death.

The extrinsic (Death Receptor-Initiated) Pathway
•Initiated by engagement of cell surface death receptors on a variety of cells
•Death receptors are members of the tumor necrosis factor receptor family that contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain because it is essential for delivering apoptotic signals

Dbdbdn
•Best-known death receptors are the type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95)

B The extrinsic pathway of apoptosis, also known as the death receptor-initiated pathway, is an important mechanism by which cells can initiate programmed cell death in response to external signals. Here’s a breakdown of its key components and processes:

1. Death Receptors:
   
   • Death receptors are cell surface receptors that belong to the tumor necrosis factor (TNF) receptor superfamily.
   • Examples include TNF receptor 1 (TNFR1) and Fas receptor (CD95/APO-1).
   • These receptors contain an extracellular domain for ligand binding and an intracellular death domain.
2. Ligand Binding:
   
   • The pathway is initiated when specific ligands bind to their corresponding death receptors. Examples of ligands include TNF-alpha (binds to TNFR1) and Fas ligand (FasL, binds to Fas).
3. Death Domain Interaction:
   
   • Upon ligand binding, the death receptors undergo a conformational change that allows them to recruit and bind cytoplasmic adaptor proteins.
   • The intracellular domain of death receptors contains a death domain, which interacts with a similar death domain found in adaptor proteins such as FADD (Fas-associated death domain protein).
4. Formation of Death-Inducing Signaling Complex (DISC):
   
   • The recruitment of FADD and other adaptor proteins to the death domain of activated death receptors forms the DISC.
   • Within the DISC, procaspase-8 (an inactive precursor of caspase-8) is recruited and activated through proximity-induced autoproteolysis.
5. Activation of Caspases:
   
   • Caspase-8 activation within the DISC leads to the activation of downstream effector caspases, such as caspase-3 and caspase-7.
   • Activated effector caspases then initiate the proteolytic cleavage of various cellular substrates, resulting in the characteristic biochemical and morphological changes associated with apoptosis.

• Cellular Response: The extrinsic pathway of apoptosis is involved in regulating immune responses, eliminating infected or damaged cells, and maintaining tissue homeostasis.
• Regulation: The activation of death receptors and subsequent apoptosis can be regulated by various factors, including inhibitors of apoptosis proteins (IAPs) and cellular FLICE-like inhibitory protein (cFLIP), which can modulate caspase activation and cell fate decisions.

In summary, the extrinsic pathway of apoptosis is initiated by the binding of ligands to death receptors on the cell surface, leading to the formation of the DISC and activation of caspases that ultimately induce programmed cell death. This pathway is crucial for immune surveillance and maintaining tissue integrity by eliminating unwanted or damaged cells.

Lysosomal catabolism; Primary lysosomes are membrane-bound intracellular organelles that contain a variety of hydrolytic enzymes, including acid phosphatase, glucuronidase, sulfatase, ribonuclease, and collagenase

•These enzymes are synthesized in the rough endoplasmic reticulum and then packaged into vesicles in the Golgi apparatus

Primary lysosomes fuse with membrane-bound vacuoles that contain material to be digested, forming secondary lysosomes or phagolysosomes
•Lysosomes with undigested debris may persist within cell as residual bodies or may be extruded. Lipofuscin pigment granules represent undigested material derived from intracellular lipid peroxidation

Heterophagy and autophagy are two distinct processes involving the degradation and recycling of cellular components, but they differ in their mechanisms and targets:

1. Autophagy:
   
   • Definition: Autophagy is a cellular process that involves the degradation and recycling of unnecessary or dysfunctional cellular components through the lysosomal machinery.
   • Mechanism: It begins with the formation of a double-membrane structure called an autophagosome around the targeted cellular material, which can include damaged organelles, misfolded proteins, or other cytoplasmic components.
   • Function: Autophagy plays a critical role in maintaining cellular homeostasis by removing cellular debris and promoting cell survival during stress conditions such as nutrient deprivation or infection.
   • Types: There are several types of autophagy, including macroautophagy (the most studied form), microautophagy, and chaperone-mediated autophagy.
2. Heterophagy:
   
   • Definition: Heterophagy refers to the process of engulfing and digesting extracellular material, such as microorganisms or particles, by a cell.
   • Mechanism: It involves the formation of phagosomes, which are single-membrane vesicles that engulf the extracellular material.
   • Function: Heterophagy is primarily involved in immune responses, where cells like macrophages and neutrophils engulf and digest pathogens through phagocytosis.
   • Example: Macrophages engulf bacteria during infection, forming phagosomes that fuse with lysosomes to form phagolysosomes, where the bacteria are degraded by lysosomal enzymes.

• Origin of Material: Autophagy targets intracellular components, while heterophagy targets extracellular material.
• Mechanism: Autophagy involves the formation of autophagosomes and fusion with lysosomes, whereas heterophagy involves the formation of phagosomes.
• Cellular Function: Autophagy maintains cellular homeostasis and responds to stress, while heterophagy is primarily involved in immune defense and clearing external threats.

In summary, autophagy and heterophagy are both essential processes for cellular health and immune function, each serving distinct roles in cellular maintenance and defense mechanisms.

Intracellular accumulations
May be;
1.A normal cellular constituent accumulated in excess, such as water, lipids, proteins, and carbohydrates;
2.An abnormal substance, either exogenous, such as a mineral or products of infectious agents, or endogenous, such as a product of abnormal synthesis or metabolism
3.A pigment

N Substances may accumulate either transiently or permanently
•The substance may be located in either the cytoplasm (frequently within phagolysosomes) or the nucleus.
•In some instances, the cell may be producing the abnormal substance, and in others it may be merely storing products of pathologic processes occurring elsewhere in the body.

Steatosis and fatty change both refer to the abnormal accumulation of lipids within cells, most commonly in the liver. Here are some key points:

• Definition: Steatosis is the abnormal retention of lipids within a cell, which can disrupt cellular function.
• Common Causes: Alcohol abuse, obesity, diabetes, and metabolic syndrome are common causes. It can also result from certain medications, toxins, and genetic conditions.
• Pathophysiology: Excessive fatty acids enter the liver, leading to their conversion into triglycerides, which accumulate within hepatocytes (liver cells).
• Consequences: While initially reversible, prolonged steatosis can progress to more severe liver conditions, such as non-alcoholic steatohepatitis (NASH), fibrosis, and eventually cirrhosis.

• Definition: Fatty change is a term often used interchangeably with steatosis. It specifically refers to the appearance of fat droplets within the cytoplasm of cells.
• Histological Appearance: On microscopic examination, fatty change is characterized by clear vacuoles within the cell cytoplasm. In the liver, this typically involves hepatocytes.
• Reversibility: Fatty change can be reversible if the underlying cause is addressed. However, chronic fatty change can lead to permanent cellular damage and scarring.

• Diagnosis: Diagnosis typically involves imaging studies (e.g., ultrasound, CT scan, MRI) and may be confirmed with a liver biopsy showing fatty infiltration.
• Management: Addressing the underlying cause is crucial. This may involve lifestyle changes (diet, exercise, weight loss), managing diabetes, discontinuing alcohol or offending drugs, and monitoring liver function.

Understanding the mechanisms and implications of steatosis and fatty change is important for the prevention and management of liver disease.

Certainly! The uptake and secretion of lipids and their accumulation in tissues involve a complex interplay of various biochemical pathways and molecules. Here’s a detailed explanation of how these components are interconnected:

• Dietary Fats: Triglycerides and cholesterol esters are ingested and broken down by pancreatic lipases in the intestine.
• Absorption: Fatty acids, monoglycerides, and cholesterol are absorbed by enterocytes (intestinal cells).

• Triglyceride Reassembly: Within enterocytes, absorbed fatty acids and monoglycerides are re-esterified to form triglycerides.
• Chylomicron Assembly: These triglycerides, along with cholesterol and apoproteins (such as apoB-48), form chylomicrons, which enter the lymphatic system and then the bloodstream.

• Chylomicrons: Transport dietary triglycerides to peripheral tissues.
• Lipoprotein Lipase (LPL): An enzyme on the surface of endothelial cells hydrolyzes triglycerides in chylomicrons into free fatty acids and glycerol.
• Free Fatty Acids (FFAs): Taken up by tissues (muscle for immediate energy or adipose for storage).

• Triglyceride Formation: In adipocytes, FFAs are re-esterified with glycerol (derived from glucose metabolism via alpha-glycerol phosphate) to form triglycerides.
• Lipid Droplets: Stored as lipid droplets within adipose cells.

• Hormone-Sensitive Lipase (HSL): Activated during fasting or exercise, HSL breaks down stored triglycerides into FFAs and glycerol.
• FFA Release: FFAs are released into the bloodstream, bound to albumin, for transport to energy-demanding tissues.

• FFA Uptake: The liver takes up FFAs from the blood.
• Triglyceride Synthesis: FFAs are converted back into triglycerides and packed into Very Low-Density Lipoproteins (VLDL).
• VLDL Secretion: VLDL transports endogenously synthesized triglycerides and cholesterol esters to peripheral tissues.

• Beta-Oxidation: In the liver, FFAs undergo beta-oxidation to produce acetyl-CoA.
• Ketogenesis: Excess acetyl-CoA is converted into ketone bodies (acetoacetate, beta-hydroxybutyrate) which are released into the bloodstream as an alternative energy source.

• Cholesterol Esters: Formed by the esterification of cholesterol with fatty acids.
• Lipoprotein Role: Cholesterol esters are transported by lipoproteins (e.g., LDL and HDL) to and from tissues.

• Excess FFAs: Chronic excess of FFAs can lead to their accumulation in the liver as triglycerides, causing hepatic steatosis (fatty liver).
• Pathological Consequences: Lipid accumulation can lead to cell dysfunction, inflammation, and fibrosis, potentially progressing to conditions like non-alcoholic fatty liver disease (NAFLD) and cirrhosis.

• Dietary lipids are absorbed and transported by chylomicrons.
• Lipoprotein lipase facilitates the uptake of fatty acids into tissues.
• Fatty acids are stored as triglycerides in adipose tissue and mobilized during energy demand.
• The liver plays a central role in processing and distributing lipids via VLDL and producing ketone bodies during fasting.
• Cholesterol esters are transported by lipoproteins to maintain cellular function.
• Lipid accumulation can result from metabolic imbalances, leading to conditions like steatosis.

Understanding these interconnected pathways is crucial for managing metabolic health and preventing lipid-related diseases.

Cholesterol esters are formed when cholesterol is esterified with fatty acids, making them more hydrophobic and suitable for transport and storage in lipoproteins.

Cholesterol and cholesterol esters
Accumulation of these are seen in;
•Atherosclerosis
•Xanthomas
•Inflammation and necrosis: During inflammation and cell injury, cellular membranes break down, releasing free cholesterol and cholesterol esters.
•Foam Cells: Macrophages ingest these lipids and transform into foam cells, contributing to the inflammatory response and tissue necrosis.
•Cholesterolosis.: Cholesterolosis refers to the accumulation of cholesterol-laden macrophages (foam cells) in the gallbladder.
•Appearance: The gallbladder mucosa exhibits yellowish cholesterol deposits, often referred to as “strawberry gallbladder” due to its appearance.
•Niemann-Pick disease, type C: Niemann-Pick disease, type C, is a lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes, which are involved in cholesterol trafficking within cells.
•Pathophysiology: The defective transport leads to the accumulation of unesterified cholesterol and other lipids in lysosomes, affecting various organs, particularly the liver, spleen, and brain.

What do intracellular accumulations if proteins usually appear as in the cytoplasm?

Protein Reabsorption droplets in proximal renal tubules are seen in what diseases?
What are Russel bodies

Proteins
•Intracellular accumulations of proteins can occur due to various reasons, including increased synthesis, defective degradation, or impaired transport. Intracellular accumulations of proteins usually appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm
•Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with proteinuria
•Defects in protein folding may underlie some of these depositions: Defective Protein Folding
•Mechanism: Proteins must fold into specific three-dimensional structures to function properly. Defects in protein folding can lead to the accumulation of misfolded proteins.
•Pathology: Misfolded proteins can aggregate and form inclusions within cells. Diseases associated with defective protein folding include neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).

•synthesis of excessive amounts of normal secretory protein ( Russell bodies): Excessive Synthesis of Normal Secretory Proteins (Russell Bodies)
•Context: Seen in plasma cells producing large amounts of immunoglobulins.
•Mechanism: When plasma cells synthesize excessive amounts of immunoglobulins, the proteins accumulate in the rough endoplasmic reticulum (ER). These accumulations appear as large, eosinophilic inclusions called Russell bodies.
•Pathology: While Russell bodies are generally not harmful, they indicate an overactive immune response and can be seen in conditions such as chronic inflammation or multiple myeloma.

Dystrophic calcification
•Deposition occurs locally in dying tissues, it occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism
•It is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat.
•Calcification is almost inevitable in the atheromas of advanced atherosclerosis

Dystrophic Calcification
•Context: Occurs in necrotic or damaged tissues despite normal serum calcium levels.
•Examples: Calcification in atherosclerotic plaques, damaged heart valves, and areas of caseous necrosis in tuberculosis.

Morphology
•Histologically calcium salts have a basophilic, amorphous granular, sometimes clumped, appearance.
•Heterotopic bone may be form with time
•Progressive acquisition of outer layers may create lamellated configurations, called psammoma bodies

Pathological calcification can be identified histologically by its characteristic features:

•Basophilic, amorphous granular appearance: Calcium deposits are blue-staining(basophilic), amorphous, and granular under H&E (hematoxylinand eosin) staining.•Heterotopic bone formation: Chronic calcification can lead to the formation of bone tissue in abnormal locations. Over time, chronic calcification can induce a local osteogenic response, leading to the formation of bone in soft tissues.•Histology: This newly formed bone resembles normal bone histologically, •Psammoma bodies: These are laminated, calcified structures commonly seen in certain tumors and chronic conditions. These structures are formed by the progressive layering of calcium and other minerals around a central nidus, often seen in slow-growing tumors or chronic inflammatory conditions.•Common Locations: Psammoma bodies are commonly found in certain types of cancers such as:•Papillary Thyroid Carcinoma•Serous Papillary Cystadenocarcinoma of the Ovary•Meningiomas•Mesotheliomas

Metastatic Calcification
•Context: Occurs in normal tissues due to hypercalcemia (elevated serum calcium levels).
•Causes: Hyperparathyroidism, chronic renal failure, vitamin D intoxication, and certain cancers.
•Common Sites: Lungs, kidneys, stomach, and blood vessels. Occurs widely throughout the body but principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins

•These tissues lose acid and therefore have an internal alkaline compartment that predisposes them to metastatic calcification

Metastatic calcification
•Occurs in normal tissues whenever there is hypercalcemia
•Four principal causes of hypercalcemia:
1.Increased secretion of parathyroid hormone (PTH)
2.Destruction of bone tissue,
3.Vitamin D-related disorders,
4.renal failure

Amorphous refers to a structure that lacks a defined, regular, or crystalline form. In the context of pathological calcification, “amorphous” describes the appearance of calcium deposits that do not have a distinct shape or organized pattern. These deposits appear as irregular, granular aggregates under the microscope.

In histological sections stained with hematoxylin and eosin (H&E), amorphous calcium deposits stain blue (basophilic), making them distinguishable from other tissue components.look like grains instead of well formed crystals

Dystrophic Calcification: Amorphous calcium deposits can be seen in areas of necrosis or tissue damage. These deposits often appear irregular and granular within the affected tissue.•Metastatic Calcification: In conditions of hypercalcemia, amorphous calcium deposits can form in normal tissues, such as the lungs, kidneys, and stomach. These deposits are not organized into a crystalline structure

Here’s how the pathogenesis typically unfolds:

1.Initiation (or Nucleation): This phase involves the initial formation of calcium phosphate crystals. It can occur either intracellularly (within cells) or extracellularly (outside cells).2.Propagation: Once initiated, the crystals can grow and propagate, leading to further deposition of calcium phosphate minerals. This process can disrupt normal tissue architecture and function.3.Final Common Pathway: Ultimately, the deposition results in the formation of crystalline calcium phosphate minerals, often in the form of apatite, which is a mineral form of calcium phosphate commonly found in bone.

Pathological calcification can occur in various tissues and organs, such as blood vessels (arterial calcification), kidneys (nephrocalcinosis), joints (calcific tendinitis),

Pathogenesis
•Final common pathway is the formation of crystalline calcium phosphate mineral in the form of an apatite
•Two major phases: initiation (or nucleation) and propagation occurring either intracellularly and extracellularly