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Define pathology

Scientific study of the structural and functional changes in cells, tissues and organs that are seen in disease.


What is the difference between cytopathology and histopathology?

In cytopathology the specimens consist of disaggregated cells rather than tissue. These specimens can be collected rapidly by non-invasive or relatively minimally invasive tests (fine needle aspirates, effusions, cervical smears, sputum and urine).


What do chemical pathologists study?

Disturbances in metabolic processes e.g. endocrinology, lipidology, diabetes, thyroid disease and other areas of clinical services


List 7 causes of cell injury and death

Physical agents
Chemical agents and drugs
Immune mechanisms
Dietary insufficiencies and dietary excess
Genetic abnormalities e.g. inborn errors of metabolism


What sort of physical agents can cause cell death?

direct trauma, extremes of temperature, radiation, sudden changes in atmospheric pressure, electric currents


Define hypoxia

A deficiency in the amount of oxygen reaching the tissues, due to any cause.


What are the three most biologically important free radicals?

OH. (hydroxyl, the most dangerous)
O2.- (superoxide)


List some targets of cell injury

cell membranes - plasma and organelle's e.g. lysosome
proteins - structural and functional


Explain the mechanism of reversible hypoxic injury

1. Cell deprived of oxygen
2. Decreased production of ATP by oxidative phosphorylation
3. intracellular Na+ concentration increase
(b) Water flows into cell due to high Na+ concentration (oncosis)
(c) Ca2+ enters cell -> damage of cellular components
(d) glycolysis pathway activation -> decreased cellular pH
(e) change in pH -> altered enzyme activity and chromatin clumping
(f) ribosome detach from the ER (attachment is an energy-requiring process) - protein synthesis is disrupted
(g) Intracellular accumulations of fat and denatured proteins can occur


Explain the mechanism of irreversible hypoxic injury

Same as reverisble, but at some point (not well understood) the damage becomes irreversible and the cell dies (most cells die in hypoxia by oncosis). Although it is unclear what actually kills the cell, the key event is the development of profound disturbances in membrane integrity -> massive influx of Ca2+.


What is ischaemia-reperfusion injury?

The damage that can be caused by return of blood flow to a tissue that has been subjected to ischaemia but is not yet necrotic.


Define ischaemia. What is the difference between hypoxia and ischaemia?

Ischemia is an insufficient supply of blood to an organ, usually due to a blocked artery, but can also be caused by reduced venous drainage. Therefore hypoxia is an insufficiency of OXYGEN, whereas ischaemia is an insufficiency in BLOOD (and therefore oxygen AND metabolic substrates) to a tissue. Ischaemia therefore causes injury more rapidly and severly than hypoxia.


What is the mechanism of cyanide toxicity?

Cyanide binds to mitochondrial cytochrome c oxidase, the last complex in the electron chain, and competitively inhibits it - blocks oxidative phosphorylation


When are free radicals produced?

Particularly in:
1. Chemical and radiation injury
2. Ischaemia-reperfusion injury
3. Cellular aging
4. At high oxygen concentrations


What types of cellular damage do free radicals cause?

Lipid peroxidation of membrane lipids
Protein, carbohydrate and nucleic acid damage


How does the body defend itself against free radicals?

The anti-oxidant system consists of:
1. Enzymes - SOD (O2.- -> H2O2, catalases and peroxidases (H2O2 -> H20 and O2)
2. Free radical scavengers - Vitamin A, C, E and glutathione
3. Storage proteins that sequester transition metals in the extracellular matrix e.g. transferrin and ceruloplasmin sequester iron and copper which catalyse the formation of free radicals


Describe the function of heat shock proteins

They recognise abnormal proteins and repair them by ensuring they fold correctly. If this isn't possible then they are destroyed. Therefore they play a key role in maintaining protein viability during cell injury. Ubiquitin is one form of HSP.


Define oncosis

Cell death with swelling. The spectrum of changes that occur prior to death in cells injured by hypoxia and some other agents.


Define necrosis

The MORPHOLOGIC changes that occur after a cell has been dead for some time e.g. 4-24 hours. These changes are due to to progressive degradative action of enzymes on the lethally injured cell N.B. necrosis describes the morphologic changes and is not a type of cell death i.e. it is an appearance not a process.


Describe the appearance of coagulative necrosis. When does it occur?

It occurs in most solid organs when the cause of death is ischameia.


Describe the appearance of liquefactive necrosis. When does it occur?

It occurs when cell death is associated with large numbers of neutrophils -> release of their proteolytic enzymes


Describe the appearance of caseous necrosis. When does it occur?

This is a special type of necrosis that only occurs under certain circumstances. It looks like soft cheese to the naked eye and is characterised by amorphous (structureless) debris. It is particularly associated with infections, especially TB. When this pattern of necrosis is seen it is often associated with a particular form of inflammation known as "granulomatous".


Describe the appearance of fat necrosis. When does it occur?

This occurs when there is destruction of adipose tissue. It is most typically seen in acute pancreatitis, where lipases are released which acts on the adipose tissue of the pancreas and fat elsewhere in the abdominal cavity.
Fat necrosis causes the release of free fatty acids which can react with calcium to form chalky deposits (calcium soaps) in fatty tissue. These can be seen by naked eye and on X-ray.
Fat necrosis can also occur due to direct trauma to fatty tissue, especially breast tissue. After it heals it can leave an irregular scar that can mimic breast cancer.


Define apoptosis

Cell death with SHRINKAGE. Cell death induced by a regulated intracellular program where a cell activates enzymes that degrades its own nuclear DNA and proteins. This is an ENERGY DEPENDENT process.


Describe the process of apoptosis and appearance under the light and electron microscope

Light microscope - shrunken and intensely eosinophilic cells, chromatin condensation, pyknosis and karyorrhexis are seen.
Electron microscope - cytoplasmic BUDDING (not blebbing as in oncosis) which progresses to fragmentation into apoptotic bodies containing organelles, cytoplasm and often nuclear fragments. These are eventually removed by macrophage phagocytosis.


How does necrosis and apoptosis differ?

Necrosis is the morphologic appearance of dead cells under the microscope and is therefore an appearance not a process. Apoptosis is a process of intracellular programmed cell death.


Define gangrene

A clinical term for necrosis that is visible to the naked eye.


What types of gangrene are there? What are their differences?

Dry - necrosis is modified by exposure of air -> drying )
Wet - infection with a mixed bacterial culuture


Define infarction

An area of cell death (ischaemic necrosis) caused by obstruction of a tissue's blood supply.


What types of infarction are there? In general why do infarcts occur?

Red and white infarcts. Most infarctions are due to thrombosis or embolism. They can occasionally be caused by external compression of a vessel (e.g. by a tumour or within a hernia) or by twisting vessels (volvolus or testicular torsion).


List three molecules that are released by injured cells

Potassium, enzymes and myoglobin


What can cause an abnormal cellular accumulation of water and electrolytes?

Hydropic swelling is caused by an osmotic imbalance (it is not hypertrophy which is swelling without water involvement). It occurs when the energy supply to the cell is cut off.


What can cause an abnormal cellular accumulation of lipids - steatosis?

In the liver this can be caused by: alcohol abuse, diabetes, obestiy and toxins (e.g. carbon tetrachloride). Mild steatosis is reversible and doesn't seem to have any effect on function -> clinically asymptomatic. The liver looks golden rather than red.
Abnormal acumulations of insoluble cholesterol (onyl eliminated through liver) are seen in membrane-boudn droplets in macrophages and smooth muscle cells within atheroschlerotic plaques (called foam cells) and in macrophages in the skin and tendons of people with hyperlipdiaemias (inherited or acquired) - where the macrophages form small masses called xanthomas.


What characteristic abnormal cellular accumulation of proteins can be seen?

Proteins are seen in eosinophilic droplets or aggregates in the cytoplasm.
1. Mallory's hyaline is a damaged protein seen in hepatocytes in alcoholic liver disease, due to the accumulation of keratin filaments.
2. alpha-1 trypsin accumulation within the ER of hepatocytes.


What can cause an abnormal cellular accumulation of pathological pigments?

They can be normal cellular pigments (e.g. melanin) or exogenous pigments.


What are the two broad categories of pathological calcification?

Dystrophic calcification - by far the most common
Metastatic calcification


What is dystrophic calcification?

Local calcification caused by a local change or disturbance in the tissue which favours the formation of hydroxyapatite crystals. This can occur in areas of dying tissue, atherosclerotic plaques, in ageing or damaged heart valves and in tuberculous lymph nodes. This can cause organ dysfunction.


What is metastatic calcification?

Systemic disturbance whcih results in hydroxyapatite crystals being depostitied in normal tissues throughout the body. This occurs when there is hypercalcaemia secondary to disturbances in calcium metabolism. It is usually asymptomatic but can be fatal.


What are the principal causes of metastatic calcification?

1. Increased secretion of PTH resulting in bone resorption
(i) primary - due to PTH hyperplasia or tumour
(ii) Secondary - due to renal failure and retention of phosphate
(iii)ectopic - secretion of PTH-related protein by malignant tumours (e.g. carcinoma of the lungs)
2. Destruction of bone tissue:
(i) primary tumours of bone marrow e.g. leukaemias, multiple myeloma
(ii) Diffuse skeletal metastasis
(iii) Padget's disease of bone - increased bone turnover
(iv) immobilisation - removes stimulation for bone formation whilst bone resorption continues


Describe the role of telomeres in cellular ageing and senescence

Telomeres are found at the ends of chromosomes and are shortened with each replication of the cell. When they reach a critical length the cell can no longer divide - this is called replicative senscence.


Describe three effects that chronic excessive alcohol intake can have on the liver

Fatty change - excess synthesis of TAG and decreased NAD+ for lipid oxidation
Acute alcohol hepatitis - direct toxic effects (acute)
Cirrhosis - hard, shrunken liver


Cells normally maintain their internal conditions to mildly altering external conditions by homestasis. When conditions are more severe cells can undergo morphological and physiological adaptations in an attempt to remain viable. What happens to cells when they reach the limits of their adaptive response?

They may show evidence of reversible injury or become irreversibly injured and die.


What factors determine the degree of damage to a cell?

Type of cell
Duration of unfavourable environment
Severity of injury
Type of tissue involved ( e.g. skeletal muscle vs neurone)


The length of time that cells can tolerate hypoxia varies. Give an example of a cell that can only tolerate hypoxia for a few minutes and one that can tolerate it for a number of hours.

Few minutes - some neurones
Number of hours - dermal fibroblasts


List the four classifications of causes of hypoxia

1. Hypoxaemic - low arterial content of oxygen e.g. low pO2 at high altitudes
2. Anaemic - decreased ability of Hb to carry oxygen e.g. anaemia, CO poisoning
3. Ischaemic - interruption to blood supply e.g. thrombus or heart failure
4. Histiocytic - inability to use oxygen in cells due to disabled oxidative phosphorylation enzymes e.g. cyanide poisoning


List some chemical agents and drugs that can cause cellular damage

Hypertonic glucose or salt concentrations
High oxygen concentrations
Illicit drugs
Therapeutic drugs


What are the two main immune mechanisms that can cause cellular damage?

1. Hypersensitivity reactions - host tissue injured secondary to an over vigorous immune reaction e.g. urticaria (hives)
2. Autoimmune reactions - failure of immune system to recognise self as self e.g. Grave's disease


Describe the normal intracellular and extracellular concentrations of Ca2+

Intracellular concentration is low 10^-7 normally and extracellularly is 1.5mM. It is a very large concentration gradient. Inside the cell Ca2+ is stored within the ER and mitochondria.


What is the consequence of membrane leakiness?

Ca2+ influx from mitochondria, ER and extracellular fluid. Ca2+ is biologically very active and activates ATPases -> further decreasaed ATP levels, phospholpases -> further membrane damage, proteases -> breakdown membrane and cytoskeleton and endonucleases -> clumping of chromatin. Damage to lysosomal membranes -> lysosomal enzymes leaking out and causing further damage to the cell.


Give a flow diagram of the events during hypoxic cell injury

1. Cell is deprived of oxygen
2. Mitochondrial ATP production stops
3. ATP-driven membrane ionic pumps run down
4. Na+ and water seep into cell
5. The cell swells and the plasma membrane is stretched (oncosis)
6. Glycolysis enables the cell to limp on for a while
7. The cell initiates a heat-shock (stress) response, which will probably not be able to cope if the hypoxia persists.
8. The pH drops as cells produce energy by glycolysis and lactic acid accumulates
9. Calcium enters cell
10. Calcium activates: phopholipases, proteases, ATPase, endonucleases
11. ER and other organelles swell
12. Enzymes leak out of lysosomes and attack cytoplasmic components
13. All cell membranes are damaged and start to show blebbing
14. At some point the cell dies, possibly killed by the burst of a bleb.


What is the mechanism for ischaemia-reperfusion injury?

It may be due to:
1. Increased production of free radicals with reoxygenation
2. Increased number of neutrophils following reinstatement of blood supply resulting in more inflammation and tissue injury
3. Delivery of complement proteins and activation of the complement pathways


How can hydroxyl free radicals be produced?

1. Lysis of water by radiation
2. Fenton and Haber-Weiss reactions (from H2O2)


Why is the Fenton reaction important in injuries where bleeding occurs?

The Fenton reaction required Fe2+ and H2O2 as substrates. Fe2+ is available due to bleeding allowing the prodcution of free radicals.


What is oxidative stress?

When there is an inbalance between free radical production and free radical scavenging which allows free radicals to build up, the cell or tissue is said to be in oxidative stress.


When are heat shock proteins produced?

They are produced by cells in large quantities during any form of stress (not just heat) - cells down-turn their usual protein synthesis and up-turn their synthesis of HSPs. However they are present in cells in small quantities in normal conditions.


How can you determine if a cell has died or not?

It is impossible to tell WHEN a cell has died and to distinguish reversible cell injury from cell death. Therefore the best way to distinguish the two is by functional rather than morphological analysis. The permeability of the cell membrane can be assessed using the dye exclusion technique, where dye is put in the cell's medium. If the dye is taken up by the cell's then they are dead.


What are the three main LIGHT microscope features can be seen in oncosis?

1. Cytoplasmic changes - reduced pink staining due to the increase in water content, this may be followed by an increase due to ribosome detachment from the ER and accumulation of denatured proteins
2. Nuclear changes - softly clumped chromatin (reversible), which may pyknosis (shrinkage), karryohexis (fragmentation), karryolysis (dissolution) of the nucleus (irreversible changes)
3. Abnormal cellular accumulations


What is karryolysis?

An irreversible change see in cellular injury - dissolution of the nucleus.


What is karryohexis?

It is an irreversible change in cellular injury, where the nucleus fragments.


What is pyknosis?

A REVERSIBLE change seen in cellular injury, involving the formation of soft chromatin clumps.


What REVERSIBLE changes have been observed in cells during reversible cellular injury?

1. Swelling - both of the cell membrane and organelles due to the Na+,K+ pump failure
2. Cytoplasmic blebs - symptomatic of the cell swelling
3. Clumped chromatin - due to reduced pH
4. Ribosome separation from the ER


What are the changes seen in IRREVERSIBLE cellular damage seen using ELECTRON microscopy?

1. Increased cell swelling
2. Nuclear changes - pyknosis, karyorrhexis or karyolysis
3. Swelling and rupture of lysosomes
4. Membrane defects
5. The appearance of myelin figures (damaged membranes)
5. Lysis of the ER
6. Amorphous densities in swollen mitochondria


What morphological differences are there between oncosis and apoptosis under the electron microscope?

Oncosis - swelling, karyolysis (dissolution)
Apoptosis - shrinkage, karyorrhexis (fragmentation)


Which are the two main patterns of necrosis?

Coagulative and Liquifactive


What determines whether coagulative or liquifactive necrosis occurs?

It is a balance between these two processes, which determines this. If protein denaturation is the main feature the proteins tend to "clump" -> solidity of dead cells and therefore coagulative necrosis. If release of active enzymes, particularly proteases, is the dominant feature the the dead tissue tends to liquefy -> liquifactive necrosis.


What is the underlying process in dry gangrene?

Coagulative necrosis


What is the underlying process in wet gangrene?

Liquifactive necrosis


Why is wet gangrene dangerous?

Bacteria from the infected tissue can enter the bloodstream causing septicaemia.


How is gas gangrene formed?

It is formed from wet gangrene, where the tissue has become infected with anaerobic bacteria that produce visible and palpable bubbles of gas within the tissue.


A motorbike accident occurs, which causes an patient's leg to be crushed underneath. The injured tissue loses its blood supply and becomes necrotic, resulting in the appearance usually of what type of gangrene?

Gas gangrene, if the tissue is colonised by anaerobic bacteria from the soil.


Where is gangrene most commonly seen in clinical practice?

Ischaemic limbs. Gangrenous tissue is dead and cannot be salvaged.


What causes red infarcts?

Occur when there is extensive haemorrhage into dead tissue. This occurs for various reasons:
1. Organs with a dual blood supply
2. Numerous anastamoses
3. Loose tissue with poor stromal support for capillaries
4. Previous congestion in tissue -> abnormal amount of blood in it
5. Raised venous pressure


Which tissues tend to exhibit red infarcts?

Bowel, brain
Dual blood supply - lungs
Numerous anastamoses - intestines
Loose tissue - lungs
Previous congestion - all tissues
Raised venous pressure - all tissues


What causes white infacts?

Infarcts in tissues with good stromal support after occlusion of an END ARTERY (the sole arterial supply to that area of the organ). The solid nature of the tissue limits the amount of haemorrhage into the dead tissue from surrounding capillaries. Histiologically they appear as coagulative necrosis.


Where do white infarcts occur?

Heart, spleen and kidneys


Infarcts can have varying consequences ranging from none to death of the patient. What do these consequences depend on?

1. Whether the tissue has an alternative blood supply e.g. lung and arm have alternatives
2. How quickly ischaemia occurs - slowly allows development of additional perfusion pathways
3. How vulnerable a tissue is to hypoxia
4. The oxygen content of the blood - anaemic patient?


What are some consequences of the leaking out of cellular contents after membrane lose their integrity?

1. Local irritation and inflammation
2. May have general toxic effects on the body
3. May appear in high concentrations in the blood, aiding diagnosis.


How can enzymes released from damaged tissues provide information on the timing of the tissue damage?

Enzymes with the smallest molecular weight are released first.


Rhabdomyolyis can occur in severe burns or trauma, with potassium depletion (during exercise in hot climates) and with alcohol and drug abuse. What is it and how does it occur?

It is when large amounts of myoglobin are released from damaged striated muscle cells. This can plug the renal tubules and cause renal failure.


What is the difference in nuclear breakdown in apoptosis as compared to oncosis?

Nuclear breakdown in apoptosis is characterised by non-random, intranucleosomal cleavage of DNA. Whereas in oncosis the DNA is chopped into pieces of random length.


What is involution?

the shrinkage of an organ in old age or when inactive, e.g. of the womb after childbirth.


When does apoptosis occur?

When cells are no longer needed to maintain a steady-state, during hormone-controlled involution and in cytotoxic T cell killing of virus-infected or neoplastic cells


What are the main differences between oncosis and apoptosis?

In apoptosis the cell membrane integrity is preserved, it is an energy-requiring process, lysosomal enzymes are not involved and it is quick (cells are gone within a few hours). Apoptosis affects a single or small number of cells and does not induce inflammation.


What are the three key phases of apoptosis?

1. Initiation
2. Execution
3. Degradation/ phagocytosis


Why is intrinsic apoptosis so named?

In this form of apoptosis mitochondria is the main player and all the apoptotic machinery is within the cell.


What do intrinsic and extrinsic apoptosis both culminate in the activation of what type of molecules?

Caspases - proteases that mediate the cellular effects of apoptosis. They cleave proteins, breaking up the cytoskeleton and initiate the degradation of DNA.


Describe the process behind intrinsic apoptosis

Various triggers (such as DNA damage (p53 protein is important in this process) or the withdrawal of growth factors or hormones), lead to INCREASED MITOCHONDRIAL PERMEABILITY and release of CYTOCHROME C from mitochondria. This interacts with APAF1 and caspase 9 to form an APOPTOSOME that activates downstream caspases.


Describe the process behind extrinsic apoptosis

External ligands, such as TRAIL and Fas bind to "death receptors" and lead to the activation of caspases independently of mitochondria.


What happens in the degradation/phagocytosis stage of apoptosis?

The cells break down into fragments called apoptotic bodies which express molecules on their surface which induce their phagocytosis by either neighbouring cells or phagocytes.


What is the role of the apoptotic molecule, p53?

It is known as the 'guardian of the genome', it mediated apoptosis in response to DNA damage


What is the role of the apoptotic molecules cytochrome c, APAF-1 and caspase 9?

Together they form the apoptosome (intrinsic apoptosis) that activates downstream caspases.


What is the role of the apoptotic molecule, Bcl-2?

Prevents cytochrome c release from the mitochondria. It therefore inhibits apoptosis.


What is the role of the apoptotic molecule, death ligands e.g. TRAIL?

They bind to death receptors and activate caspases in extrinsic apoptosis.


What is the role of the apoptotic molecule, death receptors e.g. TRAIL-R?

They are activated by extracellular death ligands e.g. TRAIL and transduce those extracellular signals into intracellular activation of caspases.


What is the role of the apoptotic molecules, capsases?

They are effector molecules of apoptosis (e.g. caspase 3). They are proteases which mediate the cellular effects of apoptosis. They cleave proteins, breaking up the cytoskeleton and initiate the degradation of DNA.


What in general causes abnormal cellular accumulations?

They are the result of deranged metabolic processes which often occur with sublethal or chronic injury. They may be reversible and they can be harmless or toxic. They can derive from:
1. Cell's own metabolism
2. The extracellular space e.g. spilled blood
3. The outer environment e.g. dust


What are the 5 main groups of intracellular accumulations?

Water and electrolytes


What are xanthomas?

A small mass of macrophages seen in the skin and tendons of people with inherited or acquired hyperlipidaemias.


What is coal worker's pneumoconiosis (lung-dust disease)?

Inhaled coal dust is phagocytosed by alveolar macrophages and causes anthracosis (blackened lung tissue) or blackened peribronchial lymph nodes which contain macrophages that have migrated form the lungs, discolouring these tissues for life. It is usually harmless, but at the high exposure of coal miner's the lungs can become fibrotic or emphysematous (abnormal enlargement of air spaces in the lungs accompanied by destruction of the tissue lining the walls of the air spaces).


Abnormal accumulation of lipofuscin are found in which type of cells? What is it caused by? What do they look like?

Lipofuscin is known as the age or wear and tear pigment and is found in long-lived cells such as neurones, mycardium and hepatocytes. It is a polymer of oxidised lipids that is a sign of previous free radical injury and lipid peroxidation. Under the microscope it appears as yellow-brown grains within the cytoplasm.


Abnormal accumulations of haemosiderin can be caused by local iron overload, give an example.

A bruise - caused by local haemorrage into the skin and subcutaneous tissues.


What is haemosiderin?

An iron storage molecule. It is derived from haemoglobin and is yellow/brown. It forms when there is a local or systemic excess in iron.


What is haemosiderosis?

It is the systemic deposition of haemosiderin in many organs, caused by a systemic overload of iron.


In what condititions is haemosiderosis seen?

Haemolytic anaemias
Blood transfusions
Haemachromatosis (genetically inherited disorder which causes an increased absorption of dietary iron in the intestines).


What occurs in the inherited disease haemachromatosis?

Iron is deposited in the skin, liver, pancreas, heart an endocrine organs. It is often associated with scarring in the liver and pancreas. Symptoms include liver damage, heart dysfunction and multiple endocrin failures, especially of the pancreas - hence the name 'bronze diabetes'. It is treated by repeated bleeding.


Where can haem be found? Therefore where can bilirubin be formed?

Haem is found in haemoglobin in red blood cells and in cytochromes. Therefore all cells in the body contain haem and can break it down into biliverdin and then toxic bilirubin.


Describe the structure of bilirubin

It is a stack of porthyrin rings that have broken open and lost their iron.


When there is bilirubinaemia, whre is bilirubin deposited?

In tissues either extracellulary or intracellulary within macrophages.


What is the theory for why the pulmonary valve never calcifies?

The theory is that the blood around the pulmonary heart valve is more acidic and the acidity prevents calcification.


What happens in acute alcoholic hepatitis?

Alcohol and its metabolites are directly toxic. A binge of alcohol can cause acute hepatitis with focal hepatocyte necrosis, formation of Mallory bodies and a neutrophil infiltrate. It can give symptoms of fever, liver tenderness and jaundice. It is usually reversible.


What is cirrhosis?

A hard shrunken liver that histologically apears as micronodules of regenerating hepatocytes surrounded by bands of collagen. It is irreversible and serious, sometimes fatal.