Degenerations and Infiltrations Flashcards
Cellular Injury
- Cellular injury can be reversible or irreversible:
- Irreversible–> Cell death
- The degenerative Changes are a continuum and the point at which injury transitions from reversible to irreversible is not always clear cut
- Try not to worry too much about individual cells , more just the patterns seen in the tissue
Generally, The effect upon a cell depends on…
(cellular Injury)
- Dose of the injurious agent acting upon the cell- (i.e. Virus, higher level of viral exposure)
- Duration for which it acts-(longer the duration, more severe) Synergistic
- The vascular flow - nutrient supply- Tissue that is highly vascularized, infectious agent will be delivered more efficiently (higher risk), but will be removed more quickly as well
- Type of cell injured: highly active cells= ↑ prone
(hepatocytes, Proxinal convoluted tubule epithelium of kidney & cardiac myocytes are most prone to injury) - Metabolically active cells are the most vulnerable to degeneration
Cell Changes characteristic of irreversible cellular degeneration
- Plasma membrane damage or damage to mitochondrial membrane which causes death as they provide E for the cell. Or of the lysosome that will cause enzymatic digestion of cellular components
- Calcium entry into the cell or reactive oxygen species accumulations–> protein breakdown and DNA damage
- Mitochondrial swelling and vacuolation (the development or formation of vacuoles)
- Lysosomal swelling (Containing cellular enzymes)
Tipping point from reversible to irrev.
4 subcellular changes are very characteristic of change from reversible to irrev.
All these changes cause ATP decrease (loss of energy dependent cellular functions)
Acute Cellular Swelling
(Hydropic Degeneration)
Movement of watery fluid into the cell
Acute cellular swelling:
- Cells may swell up like a balloon prior to their destruction
- There is a discrete bleb (vacuole) of fluid within the cytoplasm
- Causes: include mild hypoxia, viral infection (e.g. Foot & mouth disease virus) & toxins
- Mechanism: Hypoxia (for example)–> ↓ ATP production–> Na+ & H20 moves into cell & K+ moves out (Affect Na pump. Normal gradient is reversed) –>↑ osmotic pressure–> ↑ water moves into cell –> excess fluid goes into ER –> cisternae of ER distend, rupture & form vacuoles (In cell cytoplasm that become more extensive)–> extensive vacuolation in the cytoplasm (What we see under Light microscope)
- Occurs commonly in highly active cells: hepatocyte, renal tubular epithelium & pancreatic acinar cell
- Cells swell up like a balloon prior to death of cell
- Mild hypoxia, some imp. Viral infections and toxins will cause hydropic degeneration
Pathological Features
(Hydropic Degeneration)
Rare to see this as a surgeon because either the animal heals or worsens (moves on to subsequent stages)
Liver is a good organ to look at for these changes: Pale liver (hydropic degen.)
Pathological Features- First stage of cell injury & mildest, earliest detectable degenerative change –> impairment of cell membrane integrity; may be a momentary phenomenon–> quickly to more serious damage
- Gross: somewhat paler than normal; on sectioning, may slightly bulge
- Microscopic: moderate swelling of the individual cells
- Rupture of adjacent cells–> formation of vesicles (blisters)
Ex:
1) virus damaging the cell and directly affecting Na/k pump
2) Accumulation of aqueous in the ER (sodum and water move into cell and K+ out of the cell) - see distended cisternae of ER
3) get cytoplasm swelling and extensive vacuolation (recognize at electron micro. level)
All animals ultimately die as a consequence of K+ leaving cells
Mucoid (Myxoid/Myxomatous) Degeneration
- Degeneration of connective tissue (very tissue specific) involving deposition of mucinous (myxoid) material in ECM –> changes in its tensile quality of CT –> slimy & gelatinous instead of collagenous. collagen is transformed to mucous structure
- Some are very tissue specific: mucoid or myxoid-synonyms for mucous-degeneration of tissues so that the collagen is turned into mucus like substance
- Most important example= valvular endocardiosis- degeneration affects heart valves (valve is no longer blood-tight which results in backflow of blood –> atrium) –> progressive cardiac failure
- -osis: degeneration (endocardiosis–> degeneration of heart valve)
- Very common in Cavalier King Charles Spaniel or older dogs
- Turbulent blood flow can –> jet lesions in the atrium (backflow hitting the same spot of tissue). Rather than a normal heart valve where every time the heart contracts the valve forms a blood tight seal, in this case the valve is very mishapen and irregular (slimy and mucinous). Eveytime the heart contracts it is no longer a blood tight seal, get a retrograde of blood from the ventricle back into the atrium. everytime the heart contracts blood is leaking back from ventrivle to atrium and putting progressive strain on the heart. Resulting in progressive cardiac failure. Clue we use–> look for mishapen part of the valve. but when blood leaks backwards it causes progressive strike on the atrium and causes scar tissue to form–> JET LESIONS
Histo: Pale blue tissue is mucoid material. Most of valve is replaced by poor mucoid material. mishapened nodular. Collagen will stain pink on H&E stain, may still see a little. most of the valve is replaced by this poor quality mucoid
Not to be confused with Mucous metaplasia of epithelium:
- Causes similar gross appearance but this is an adaptive response (beneficial) not a pathology
- Not really a degeneration
- Irritated wet mucous membranes & mucous glands ↑–> ↑ mucin production–> lubrication & protection –> Soothes inflamed surfaces, Traps and dilutes harmful agents, Carries specific antibodies against infectious agents & Provides means for their removal
- HIsto: can see goblet cells producing mucus
Fatty Change
Accumulation or increase of fatty substances within cytoplasm of specific cells
E.g. liver parenchyma, kidney and heart (Think of metabolically active cells!)
- Important intracellular abnormality, can be easily recognised post-mortem- Can be easily recognized as well in exploratory surgery
- Degenerative change
- Very important as it underpins so many veterinary diseases
- DOES NOT REFER TO BODY FAT STORES: Don’t make this error. This refers to accumulations in areas of the body or the cells where you wouldn’t normally see fat accumulation! Not subcutaneous fat
Summary of normal metabolism of fat
- Catabolism of fat within the liver. Metabolized in liver to triglycerides and transported out as lipoproteins
- The various disease causing fatty change is associated with altering a part of this 3 step process
Gross Appearance
(Fatty Change)
Gross Appearance:
- Liver: Size may ↑ greatly, tan- yellowish colour, very prone to rupture with slight pressure (friable); on cutting through the surface the underlying parenchyma bulges outwards; parenchyma is dull in appearance; yellowish and greasy (adheres to knife)
- Kidney: cortex appears paler (Note: cats normally have fatty kidneys). Species difference: normally expect to see some fat in convoluted tubules in cats
- Heart: flabby with streaks in the papillary muscles. Heart is less contractile and has streaking in papillary muscle. Striping. Heart is a late change we don’t often see
Microscopic Appearance
(Fatty Change)
- Liver & Kidney: globules/ vacuoles of varying size in cytoplasm of teh cells, nucleus = normal but is pushed to the periphery
- Heart: tiny groups of vacuoles dispersed along the myofibrils. Smaller vacuoles in the heart, by the time it get to the heart it will already be pretty ill. They won’t survive much longer so the change is still in early stage in relation to the heart
- Identification: Fat dissolves in the alcohols used in slide processing –> empty vacuoles ∴ to prove fat is present need to stain frozen sections using Oil-Red-O or Sudan black. Should see some lipidosis.
***Difference to hydropic change: in fatty change there is a single large vacuole in the cell pushing membrane (like adipocytes), where in hydropic you see multile vacuoles in a cell
DIstribution of Fatty Change
- Fatty change affecting the liver may be diffuse (e.g. Metabolic disease) or zonal (e.g. Circulatory disease)
- Zonal fatty change in congestive heart failure leads to a ‘nutmeg’ liver with fatty change in periportal areas and congestion in periacinar areas
- Resembles nutmeg spice. Zonal type of fatty change with an animal with a failing heart. Redder areas are congested areas. In failing heart, venous return is poor so more blood is pooling in the liver and stagnating. Liver cells in the stagnated areas are dying or dead so few there. Liver cells that are closer to hepatic portal vein are more viable but progressively undergo fatty change as they are provided with more venous blood around triads –> pattern in fatty change
- DIstribution:
-Diffuse- starvation (pale fatty liver)
- zonal - chronic passive congestion (more nutmeg spice pattern, cow with heart failure)
- Focal- See changes where liver is fixed to diaphragm. With movement you get damage to that area of liver due to tension
Dietary Factors
(Causes of Fatty Changes in the Liver)
Dietary Factors
- Starvation –> ↑ mobilisation of fat- liver can’t cope with them all- so stores some here as neutral fats
- Overeating - obesity (intake> energy expenditure)- fat is temporarily stored prior to –> body fat stores
- Both overeating and starvation cause excess delivery of fat to the liver
- Lipotrope derangement – lipotropes (Lipotropic compounds are those that help catalyse the breakdown of fat during metabolism in the body) = substances which hasten removal of fat from liver cells. E.g. AAs that facilitate conjugation of the fat with proteins–> lipoprotein that is excreted from the cell.
- Lipotropes: assist in export of fat from liver to fat stores
- Deficiency of these e.g. choline and methionine (conjugating aa’s) in the diet –> fatty change within the cells
- will lead to decrease in efficiency of export of fat from liver
- body is catabolising fat stores to liver
Metabolic Disease
(Causes of Fatty Changes in the Liver)
Disease associated with deranged carbohydrate metabolism. Unbalanced carbohydrate metabolism –> no glucose for uptake into tissues ∴ Alternative energy sources used. i.e. fat is mobilised from reserves like starvation
- Diabetes mellitus a deficiency (or cells refractory to its influence) of insulin which is required for cellular glucose utilisation. Cells cannot use glucose so demand for alternative energy lead to fat mobilisation
- Ketosis in ruminants, excess demand on glucose reserves
- In sheep caused by twin lambs (called ‘pregnancy toxaemia’)- “twin lamb disease”
- In high-yielding dairy cows shortly after parturition shortage of energy
- Liver failure as consequence of degeneration
Hypoxia
(Causes of Fatty Changes in the Liver)
Hypoxia (Changes in oxygen delivery)
Any condition that ↓ oxygen supply to the tissues–> fatty change in the liver
- Anaemia (↓ circulating RBCs) caused by sustained loss of erythrocytes from the vessels as in chronic haemorrhage or the excessive destruction of erythrocytes within the vessels ( haemolysis )
- Ischaemia (↓ blood supply to a tissue) & chronic venous congestion (slowing of blood flow through the vasculature ) due to a failing heart-Circulatory disease leading to fatty change
Toxins
A large number of toxins–> fatty change in the liver which tends to be a more severe form of cellular swelling
- Bacterial & fungal toxins either produced in the bloodstream from circulating bacteria (septicaemia/bacteraemia) or produced elsewhere and absorbed into the bloodstream
- Chemical toxins such as CCl4, phosphorus, arsenic and lead
- Some plant poisonings will cause fatty change in the very early stages of poisoning
Hyaline Degeneration
Descriptive term: hyaline = ‘glassy’/ ‘frosty’ appearance- applies to several types of degeneration or infiltration
- tissues being converted to a structureless and pinkish red material that looked somewhat like frosted glass- name has been used descriptively to capture that change
- what they were seeing was degeneration of protein which is what this hyaline change is
Microscopic: structureless and stains pinkish red with eosin in H&E
This can occur in:
- In skeletal muscle: degeneration –> structureless appearance of muscle fibres & homogeneous, pale appearance of the cell cytoplasm. skeletal muscle contains a high amount of protein. structureless ones under micro. are undergoing hyaline degeneration - “white muscle disease” is associated sometimes with hyaline degenration of muscle
- In renal failure & proteinuria, hyaline casts are casts of proteins which have escaped across the glomerulus of the failing kidney. result of an animals kidneys starting to fail. protein in urine will tend to form a cast in teh collecting duct–> hyaline cast (brown glass, frosted glass, semi-opaque appearance)
- In lungs if there’s severe alveolar damage–> proteinaceous leakage–> protein precipitates in alveoli and forms a layer of hyaline material called hyaline membranes- impedes gaseous exchange. when there is extensive damage (alveolar damage) this allows a large of proteins to exude into the airways and forms a thick layer of coagulated protein –> hyaline membranes. Microscopic view of alveoli. Excessive protein to leak into the airways. Forms thick coagulant over damaged alveoli. This would indicate profuse lung disease. Compromise of blood/gas exchange
- Described early that tissues being converted into a structureless, pink material
–> really the degeneration of protein leads to this hyaline appearance
-when skeletal muscle degenerates (high amount of protein) –> degenerate into hyaline
Fibrinoid Degeneration
- Tissue Specific. Fibrin–> think of blood vessels
- Degeneration associated with blood vessel walls
- Consequnces of this: ↑ risk of haemorrhage
- Microscopic: appears as Fibrin-like red smudging
- Consists of degenerated muscle & elastic fibres & protein precipitating around the degenerated fibres
- When a blood vessel degenerates. Fibrinoid degeneration represents this accumulation of dense pinkish material (protein). Accumulating within the wall of the blood vessel. Relating to degenerate smooth muscle within the blood vessel wall. Reason we say Fibrinoid is that likely this material is to include fibrin itself. Coagulating fibrinogen and degenerating smooth muscle together –> fibrinoid degeneration. Can happen in animals anywhere where the blood vessel is damaged. Good example: localized hypersensitivity reaction that is localized to the vessel walls
- Suggests either:
- Local hypersensitivity reaction (type 3 hypersensitivity/ Arthus reaction)-Type III hypersensitivity occurs when there is an excess of antigen, leading to small immune complexes being formed that fix complement and are not cleared from the circulation. It involves soluble antigens that are not bound to cell surfaces (as opposed to those in type II hypersensitivity)
Arthus reaction: where immune complexes are launching within blood vessel walls and resulting in degeneration of the blood vessel
- Damage due to hypertension (↑ BP)- more what you see in animals (common more to cats)
- normally when BP rises, the vessel responds by proliferation of smooth muscle, but degeneration of this leads to fibrinoid degeneration (type of degeneration associated with blood vessels)
Glycogen Storage
- Degeneration associated with accumulation of glycogen in cells
- Seen particularly in renal tubules in:
- Diabetes mellitus due to deranged carbohydrate metabolism
- In the liver of animals on prolonged corticosteroid therapy or
↑ level of circulating corticosteroid due to underlying disease
- Principal veterinary asociation is level of corticosteroid exposure (therapeutic or secondary to hyperadrenocorticalism) - Animals that are receiving medicinal corticosteroids over a long period of time or hyperadrenocorticism
- Glycogen is normally present in ↑ amounts in the liver & muscleas a utilisable energy source
- Moderate amounts of glycogen don’t alter gross appearance much but when glycogen accumulates to the level where it interferes with the function of the individual liver cells–> swelling/ pallor of the liver. Liver will become swollen and lighter in color.
- Microscopic: foamy cytoplasmic vacuoles in liver cells where glycogen is accumulating, similar appearance to fatty degeneration therefore must put clinical history in context, can stain specifically for glycogen using PAS. Glycogen largely leaches out of tissues when prepared, but not all, you will see vacuolated cells, but do not confuse with fat!! Use proper stains to tell difference. Periodic Acid shift stain
Cellular Inclusions
-still in reference to abnormalities in a cell
Viral Inclusion Bodies
- Accumulations of viral nucleic acid or protein
- Nuclear, cytoplasmic or both
- Subcellular localisation indicates type of virus (this makes it important in terms of pathology)
- ex: viral inclusions in the cells of the CNS, could be distemper (intranucelar and intracytoplasmic). these inclusions in the CNS are always intranuclear
Abnormal Storage Products
- Hereditary storage diseases in which there is a missing or defective cellular enzyme, the absence of which –> Build-up of intermediate metabolites in cytoplasm
- Usually affects all tissues & is genetic ∴ usually presents early in life
- CNS is particularly vulnerable because it cannot regenerate. Abnormal storage accumulates in neurons and causes neuro disease
Amyloidosis
Amyloid is an abnormal protein that is produced in your bone marrow and can be deposited in any tissue or organ
-much less common than fatty change but like fatty change, underpins a variety of diseases
A polymerisation of abnormal peptides–> fibrillar proteins from a wide variety of sources including albumin, immunoglobulin, acute phase proteins & hormones
- Is not a single disease entity but a diverse group of disease processes
- Characterised by deposition of a heterogeneous group of proteins in one/ many organs
- The proteins mis-fold –> ‘beta-pleated fibrils’ that make up 95% of the amyloid- insoluble. Amyloid fibrils are hard to break down and as they build up can cause a lot of damage and can stop the affected tissue from working properly. Proteins misfold into B pleated sheets and then that makes that protein insoluble. Cant be broken down normally by body enzymes
- Amyloid light chains of antigens bind together and form fibrils
- Can occur anywhere in teh body but mainly the kidneys, heart, liver, spleen, nerves and GIT
- Other 5% of material derived from CT including serum amyloid P component, GAGs and proteoglycans
Primary (AL) Amyloidosis
- AL - amyloid light chain (light chain in antibodies!)
- main misfold is in the immunoglobulin light chain!
- In people, not associated with true plasma cells, but due to bone marrow
- Caused by plasma cell tumours that –> inappropriate/ excessive amounts of Immunoglobulin
- Affected animals have monoclonal gammopathy (abnormal immunoglobulin protein found in the blood) with gammaglobulin in urine (Bence-Jones proteinuria)- abnormal immunoglobin protein (known as a paraprotein) is found in the blood during standard laboratory blood tests
- Many cases in humans not caused by tumours but instead by apparently normal plasma cells in BM, but an increased number which produces excessive immunoglobulin - sometimes called Dyscrasia- rare in animals
- histo: neoplastic cells are the varied in shape ones.
- Animal with plasma cell tumor. Plasma cells are accumulating monoclonally (cloning from a single cell) as a consequence of the tumor and producing immunoglobulin light chain and that misfolds
-one can diagnose that by looking at abnormal amounts of protein in the blood or spilling over into the urine (hyaline casts in urine). can also use electrophoresis to look at the amount of abnormal protein (immunoglobulin) present in an animal with AL amyloidosis
Secondary (AA) Amyloidosis
- AA as precursor protein = serum amyloid A but also referred to as Reactive Systemic Amyloidosis
AA–> (amyloid associated) non Ig protein from the liver
- Caused by chronic inflammation:Amyloid forms as a consequence of mis-folding caused by inflammatory reactions, particularly chronic infections (e.g. in tuberculosis)
- Deposited at variety of sites in body, but one of most functional significance is amyloid deposition in the renal glomeruli of the dog and ox
- Protein deposits multifocally in the animal: RENAL AMYLOIDOSIS
- pale appearnace to the cortex
Gross Changes
(Renal Amyloidosis Pathogenesis)
- Pale cortex (as glomeruli are located cortically)
- Waxy appearance & glomeruli appear as white dots (largest in vet species)
- Will stain yellowish brown with an iodine solution–> Kidney with amyloidosis treated with iodine and sulfuric acid solution- can visualize the kidney amyloidosis
- Subsequent treatment with dilute sulphuric acid turns
them blue-purple
Microscopic Changes
(Renal Amyloidosis Pathogenesis)
- Deposition of a pink homogeneous material in the glomerulus
progressively replacing the glomerular epithelium and endothelium
- The amount of amyloid varies between individual glomeruli
- Cuffs of the same material accumulating around renal tubules
- Stains pink with Congo Red, and the amyloid fibrils appear an ‘apple-green’ colour in polarised light (Get apple green biorefringness, almost a fluorescent green)
- Amyloid protein becomes almost a waxy appearance, the protein itself stains that pink color
- Look for abnormal protein(especially in glomeruli). Reddish pink. Progressively accumulating on glomeruli basement membrane. Affecting glomeruli function and therefore filtration, losing protein in urine
- Also accumulates around the renal tubules
Hepatic Amyloidosis
Amyloid can also accumulate in the liver which becomes swollen (hepatomegaly), pale in colour & friable –> high risk of haemorrhage
-hepatomegaly: abnormal enlargement of the liver
- Amyloid also an issue if it accumulates in liver. Causing swollen and pale liver. The liver is becoming similar to fatty liver and is susceptible to rupture
- Amyloid is the material accumulating in the sinusoids. Protein is blocking the delivery of nutrients to hepatocytes.
- To diagnose the diff b/w this and fatty liver, fatty liver will float in water, this wont
Hydropic Degeneration
- excess fluid is transferred to the ER
- this swells and eventually fragments, leavinga fluid vacuole in the cytoplasm (Progressive vacuolation)
- commonly occurs in very metabolically active cells such as the hepatocyte, renal tubular epithelium and pancreatic acinar cell which have well-developed pumping mechanisms- Dependent on their function on a robust sodium pump
- This is a wholly reversible change if recognizing this after a liver biopsy, but only really if this animal is presented at this stage
- Hydropic degeneration is a feature of certain viral infections (e.g. foot and mouth disease virus) - Epithelial cells of mucosal surfaces (hooves and mouths). Occurs with certain viruses (mainly the blistering viruses)
- Rupture of adjacent cells leads to the formation of vesicles (blisters)
- Cells rupturing and fluid accumulating causing blistering, which is what we recognize
- Blister rupture releasing water (IMPORTANT CLINICAL OBSERVATION)
Mucous Metaplasia of epithelial surfaces
metaplasia: one cell type changes into another cell type
Use mucous metaplasia for An epithelium that is irritated by abrasion, etc. stimulates proliferation of goblet cells and encourages transformation of other non-mucous producing cells into goblet cells which will then produce mucous. The consequence is that more and more mucus accumulates on the surface of the epithelium. See glistening. Mucus metaplasia is not a degeneration, but really a response to an insult. Really an adaptive change that is beneficial. Lubricating and entrapping infectious foreign material. Example in pathology where a change causes an increased amount of mucus. The type of inflammation that accompanies this is catarrhal inflammation
catarrhal inflammation: An inflammatory process that occurs in mucous membranes and is characterized by increased blood flow to the mucosal vessels, edema of the interstitial tissue, enlargement of the secretory epithelial cells, and profuse discharge of mucus and epithelial debris
DIFFERENT than MUCOID DEGENERATION: which is accumulation of mucous tissue in such regions as the heart
