General Pathology

An Introduction to General Pathology

• The term pathology is derived from:
  • Pathos, or suffering
  • Logos, or reasoning/logic.
• Pathology is defined as the study of disease including:
  • Aetiology - causal factor(s)
  • Pathogenesis - the development of the disease within the body.
  • Lesions - the observable structural changes in the tissues and fluids of the body.
  • Pathophysiology - the functional changes in diseased tissues.
  • Sequel - the consequences of the disease in the body.
  • Remote effects - the effect of disease in one tissue on other tissues in the body.

Lesions

• Lesions are the abnormalities or changes seen in living tissues due to disease.
• Observed in
  • The live animal
  • Tissues surgically removed from the live animal
    • Biopsy/ excision
  • Animals soon after death
    • Necropsy, post-mortem examination.

Decription of Lesions

• Descriptions of lesions is very important
• Whole organs, tissues or individual lesions are described under headings such as
  1. Size
  2. Shape
  3. Colour
  4. Weight
     • Generally in relation to body weight
  5. Texture and Consistency
  6. Appearance of the cut surface
  7. Contents of hollow organs
  8. Position, relationships and effects on adjacent tissues

Disease

Definition and Type

• Disease is a definite morbid (illness producing) process, having a characteristic train of symptoms or signs.
  • May affect the whole body or any of its parts.
  • The disease's aetiology, pathology and prognosis may be known or unknown.
• There are two main categories of disease.
  1. Acute
     • Characterised by sudden onset and short duration.
     • The outcome of acute disease may be:
       • Death
       • Resolution due to host defence response or clinical therapy
       • Progression to chronic disease
  2. Chronic
     • Characterised by insidious onset and protracted course.
     • The outcome of chronic disease may be:
       • Progressive destruction of tissue
         • Compromises funtion and endangers life,
       • The halting of the course of disease, with tissue repair by scarring.

Factors Involved in the Development of Disease

• There are three factors which conspire with each other to produce disease.
  1. The individual animal.
     • In particular, the animal's nutritional and immune status
       • This is modified by:
         • Recent or concurrent disease
         • Previous exposure to the agent(s) responsible
  2. The disease-causing agent(s).
     • Most do not cause a uniform pattern of disease
       • Host defences are important in determining the presentation of the disease.
     • An agent's capacity to produce disease depends upon:
       • The dose
       • The virulence of the agent
     • Several agents may be involved.
       • Usually one agent debilitates, allowing others to exert a greater effect within the body
     • The presence of an agent does not necessarily mean it is the cause of the disease!
     • A pathogenic agent may be absent from the tissues, due to:
       • Clinical therapy
       • Host defence systems
  3. Environment, for example:
     • Overcrowding of animals
     • Mixing animals from differing origins
       • Carriers are allowed to infect susceptible animals.
         • Carriers are animals which harbour the pathogenic agent but do not show signs of disease.
     • Changes in management routine

Types of Agents Causing Disease

1. Infectious organisms
   • Viruses
   • Bacteria
   • Fungi
   • Parasites
2. Physical
   • Trauma
   • Pressure
   • Heat
   • Cold
   • Radiation
3. Chemical
   • Toxic organic and inorganic substances
   • Toxins produced by infectious organisms
4. Nutritional
   • Deficiencies of vitamins and trace elements
   • Excess vitamins and trace elements
5. Genetic defects
   • There is a very wide range of potential defects.
     • Some are incompatible with life
     • Others affect specific systems within the body

Aspects of Disease

• There are many aspects of a disease that must be considered in order to understand it in full.
  1. Incidence
     • How much of the disease is present?
     • Where is the disease found?
     • In what species is the disease seen?
  2. Aetiology
     • Causal agent(s)
     • Predisposing factors
  3. Transmission
     • How is the disease spread between individuals?
     • Is the disease zoonotic?
  4. Pathogenesis
     • How the causal agent(s) exert their effect within the body.
  5. Diagnosis
     • History
     • Clinical findings
       • Clinical examination
       • Clinical pathology
     • Biopsy or post-mortem examination
  6. Prognosis and Treatment
  7. Control and Prevention
     • The ideal situation

Post-Mortem Examination

• Post-mortem examination (PME) investigates the observable structural changes in the animal.
• Information relating to the disease withing the body or specific tissue is gained from PME.
  • This includes information on the disease's
    • Aetiology (cause).
    • Pathogenesis (development).
• Several types of changes are encountered at post-mortem examination.
  1. Those due to the disease
     • Lesions
  2. Those occuring immediately prior to death
     • Agonal
  3. Those occuring after death
     • Post-mortem

Techniques Involved in Pathological Examination

• Fluid examination
  • E.g. blood, urine, discharges from orifices and so on.
• Cytology
  • Examination of cells in smears, aspirates and fluids.
• Necropsy
  • Visual examination of the gross changes in the dead body.
• Histopathology
  • Microscopic examination of:
    • Tissues selected from the dead body after necropsy.
    • Biopsy/excision materials from lesions in the living animal.
• Histochemistry
  • Microscopic visualisation of enzymatic activity in tissues.
• Immunological methods
  • Specific antibody activity can be detected in tissues and fluids.
    • Examination of serum can show prior exposure to a particular infectious agent (i.e. specifice antibodies).
  • Specific antigens can be detected in tissues.
    • When linked to a marking agent (e.g. a fluorescent dye), an antibody can localise its antigen in the tissue.
• Electronmicroscopy
  • Electronmicrosopcy shows fine detail of the surfaces or internal structures of cells.
• Bacteriology/ Virology/ Parasitology
  • These techniques allow the isolation and identification of pathogenic bacteria, viruses and parasites.
• Toxicology
  • Analysis of tissues for particular poisons and toxins.

Degenerations and Infiltrations

• Degenerations and infiltrations are the morphological manifestation of an altered metabolism within the cell.
  • A particular kind of change within a cell or tissue may suggest that a specific type of alteration has occurred.
• Degenerations and infiltrations are types of structural changes.
  • These are best considered at a cellular level.
  • These structural changes are deviations from the cell's normal structure and function.
    • Parameters are outside the normal physiological range for the cell.
• Degeneration
  • The tissue cell shows some change in itself.
• Infiltration
  • Something accumulates in the cell or tissue.

Cellular Swelling

• Cellular swelling is
  • The earliest detectable degenerative change.
  • The mildest from of cellular degeneration.
  • The first stage in injury to a cell.
  • Caused by a variety of insults, e.g.
    • Lack of oxygen (anoxia) to a tissue.
    • Toxic influences.
• Is due to the impairment of the integrity of the cell membrane.
• Cellular swelling is characterised by a moderate swelling of the individual cells.
  • Due to an influx of water into the cell.

Gross Appearance

• Organs diffusely affected with cloudy swelling grossly appear pale.
  • This may be partly due to the swollen cells impeding the tissue's blood supply.
• Without cutting into an organ, it may be difficult to appreciate a gross enlargement of it.
  • Each individual cell is increased in size, meaning the entire volume of the organ is also increased.
  • E.g. on cutting the liver or kidney capsule, the underlying swollen parenchyma bulges outwards, making the cut ends of the capsule retract.
• The degree of gross swelling is not great.
  • Could be easily confused with early post-mortem changes in the organ.

Histological Appearance

• Individual cells appear somewhat swollen.
• The cytoplasm appears more red in colour in hematoxylin and eosin (H&E) stained sections.
• The nucleus of the cell remains normal.
• Cellular swelling is best histologically appreciated in the liver and kidney in damage caused by circulating toxins that are not powerful enough to actually kill the cells.

Significance of Cellular Swelling

• Cellular swelling is an important stage in degeneration.
  • Not commonly observed on its own without more serious changes
    • Not easy to identify at post-mortem unless the examination os perfomred very soon after the animal's death.
      • Early post-mortem (autolytic) change in dead tissue looks rather similar.
    • Cellular swelling is also reversible.
      • When the toxin is no longer exerting its effect, the tissue returns to normal.
    • Cellular swelling may be a transient stage in the more serious forms of degenerations which follow.

Hydropic Degeneration

• Hydropic degeneration often indicates severe cellular damage due to viruses.
  • Is a more severe or advanced form of cellular swelling.
• There are two types of hydropic degeneration, in which:
  1. The cells may swell up like a balloon prior to their destruction.
     • Balloning Degeneration
  2. There is a discrete bleb (vacuole) of fluid within the cytoplasm.
     • Vacuolar Degeneration

Ballooning Degeneration

• May occur in a variety of conditions.
  • Is particularly seen in viral conditions of epithelial tissue.
• Foot and Mouth Disease is the best example.
  • Foot and Mouth virus attacks the stratum spinosum of the epithelium of the tongue and feet.
  • Affected cells balloon up with water containing the replicating virus, swelling until they burst.
    • The fluid contained in the cells then forms microvesicles (blisters) in the stratum spinosum.
      • Blisters may later burst, shedding vast quantities of the virus.
  • On bursting, the edges of the erosions look ragged.
    • Within weeks, the germinal epithelium at the base of the erosion regenerates the epithelium, leaving no trace of a scar.

Vacuolar Degeneration

• In vacuolar degeneration, excess water is transferred to the endoplasmic reticulum (ER).
• The ER swells and eventually fragments.
  • A fluid vacuole remains in the cytoplasm.
• Commonly occurs in cells that are very metabolically active and have well developed pumping mechanisms.
  • E.g. as the hepatocyte, renal tubular epithelium and pancreatic acinar cell.

Cellular Fatty Change

• DOES NOT REFER TO THE THE FAT STORES OF THE BODY!
  • Fatty substances accumulate or increase within the cytoplams of specific cells.
  • In some instances, the fat stores may be involved in the transfer of fat to these specific cells.
• Cellular fatty change is an important intracellular abnormality.
  • Principally concerns the intracellular fat in hepatocytes.
• Fatty change is commonly seen in three organs of the body.
  • Prinicpally in the liver.
  • Also in the kidney and the heart.
  • This is because these organs are either:
    • Involved in the metabolism of fat, or
    • Dependant upon lipids as an energy source.
• Fatty change can be readily recognised at post-mortem.

Gross Appearance of Fatty Change

• Liver
  • This is the main organ involved in fatty change.
  • May be greatly increased in size.
  • Is tan to yellowish in colour.
    • Is normally reddish brown.
  • Very prone to rupture with slight pressure (friable).
  • Parenchyma bulges outwards on being freed from the constraint of the capsule when cut.
  • Parenchyma is dull, yellowish and greasy.
• Kidney
  • The cortex appears paler.
    • N.B. This is normal in e.g. the cat!
    • Diffuse paleness is not the prominent feature, unlike in the liver.
• Heart
  • Anoxia, as a result of anaemia, causes fatty change.
  • The heart is flabby.
  • Fatty change may occur as streaks in the papillary muscles.
    • I.e. those muscles furthest away from the blood supply.
  • Contractile ability is reduced, and blood is therefore not umped efficiently.

Histological Appearance of Fatty Change

• The fat either appears as globules or is contained in varying sizes of vacuoles in the cytoplasm.
  • In the heart, fat appears as groups of tiny vacuoles dispersed along the myofibrils.
  • In the liver and kidney, vacuoles tend to coalesce to form larger ones.
    • One or more large globules may fill the cytoplasm.
      • The nucleus is displaced to the periphery of the cell.
• The nucleus remains normal.
  • Nuclear changes are only seen if the degree of fatty change becomes incompatible with the continued existence of the cell.
• In hepatocytes, it is necessary to stain for fat in order to ellucidate if a vacuole in the cytoplasm is fat-containing.
  • Two further conditions may produce vacuoles in hepatocytes.
    • Vacuolar hydropic degeneration
    • Glycogen accumulation
  • Stains commonly used include Sudan 111, Sudan 1V, and Oil Red O.
    • Stain fat varying shades of orange to red.
  • Sections must be prepared differently to the routine paraffin embedding (used e.g. in H&E staining).
    • The strong solvents used in paraffin embedding dissolve the fat out of the cell.
    • When staining for fat, the tissue to be examined is frozen and sectioned in a cryostat before being stained.
      • These sections are more than twice as thick as those attained by sectioning paraffin blocks
        • There may be some overlap of cells on the section.
        • Individual cells are less clear.

Causes of Fatty Change

Dietary and Metabolic

1. Starvation
   • A reduction in dietary intake neccessitates the increased mobilisation of fat from body fat stores to meet energy needs.
   • Fat from stores is transported in the blood as fatty acids.
     • The liver cannot cope with them all properly.
       • The fatty acids are stored in the liver as neutral fats.
2. Overeating
   • When the dietary intake is greater than the energy expenditure, the fat is temporarily stored prior to movement to the body fat stores.
     • Also occurs in fat-rich diets.
3. Lipotrope Derangement
   • Lipotropes are substances which hasten the removal of fat from the liver cells.
   • Lipotropes include the amino acids that allow conjugation of fat with proteins to form the lipoprotein that is excreted from cells.
     • E.g. choline, methionine.
     • Dietary deficiency of these leads to fatty change within the cells.
   • Some poisons also prevent stages of lipoprotein formation.
     • E.g. CCl4, phosphorus and alcohol

Metabolic diseases

• Certain metabolic diseases may result in deranged carbohydrate metabolism.
• Glucose is not made available for uptake into the tissues.
  • The celles still require energy, and so alternative pathways are resorted to.
    • This leads to fatty change.
• Examples:
  • Diabetes mellitus in dogs
    • Deficiency of the hormone insulin required for cellular glucose utilisation.
  • Ketosis in ruminants
    • The body is exhorted to find another source of energy following drainage of the glucose reserves.
      • Fat reserves are mobilised and transported to the liver.
    • E.g.
      • Twin lambs in sheep
        • The condition is known as Pregnancy Toxaemia
      • Milk producion in high-yielding dairy cattle shortly afer parturiton.
        • Acetonemia

Anoxia

- an inadequate supply of oxygen to the tissues Any condition that reduces the oxygen supply to the tissues will cause fatty change in the liver. Anaemia ( a reduced numbers of red blood cells circulating in the blood ) caused by sustained loss of erythrocytes from the vessels as in chronic haemorrhage or the excessive destruction of erythrocytes within the vessels ( haemolysis ) are examples as are the various circulatory disorders such as ischaemia ( reduced blood supply to a tissue ) and chronic venous congestion ( slowing of blood flow through the vasculature ) due to a failing heart.

Toxins

. A large number of toxins will cause fatty change in the liver. In these cases, consider the fatty change to be a more severe form of cellular swelling. Among these are; a. bacterial and fungal toxins- either produced in the bloodstream from circulating bacteria (septicaemia/bacteraemia) or produced elsewhere and absorbed into the bloodstream. b. chemical toxins such as CCl4, phosphorus, arsenic and lead. c. some plant and fungal toxins, will cause fatty change in the very early stages of poisoning.

Distribution of fatty change in the liver

. The distribution of fatty change in the liver lobule tends to be throughout the whole lobule but occasionally there is a preferential localisation which may give some clue to inciting cause. Chronic venous congestion in the liver due to a failing heart ( a cause of anoxia ) will also produce fatty change. In conjunction with the fatty change the pooling of the blood in the centrilobular area due to ineffective flow back to the heart, gives a striking gross appearance of areas of yellow interspersed with red, and this has been described as a 'nutmeg liver'. The practical implication of this when found at post-mortem examination, is to examine the heart for the cause.

Significance of fatty change

It is important to remember that fatty change is reversible, provided that the underlying cause is brought under control. It may be difficult to decide whether the fatty change is due to a toxic effect or metabolic defect, from the distribution of the fat within the cell. In the former, fatty change can be considered as a more serious form of cellular swelling and you may see evidence of a further change in the cells, which is death of the cell (necrosis). But if the metabolic defect is prolonged for any period, the impairment of cellular function occasioned by the substantial amount of cytoplasmic fat, may also result in death of the cell. Wallerian Degeneration. This is a special form of fatty change in the nervous system, where damage to myelinated nerves results in the degeneration of the myelin that ensheaths them. It can be selectively stained and will be discussed further in the CNS lectures in Systematic Pathology. Extracellular accumulation of lipids Lipid may be present outside the cell in some conditions. Necrosis of cells containing lipid may release lipid into the extracellular space where they are visible. Cholesterol is released from cells or pooled from lipoproteins in crystalline form( cholesterol clefts )as a result of haemorrhage or tissue damage.

Mucoid Degeneration

4. Mucoid ( mucinous, myxomatous ) degeneration - changes in epithelial tissue or ground substance (matrix) produced by fibroblasts in connective tissue.. This is an extracellular phenomenon of some specific cells. They tend to show a bluish tinge in H&E stained sections. a. Epithelium - specifically the goblet cells of wet mucous membranes and the mucous glands themselves. It is a beneficial reaction and is not really degeneration, but an increased production of mucin. Their secretions are important as lubricants and protective substances 19 soothing inflamed surfaces, entrapping and diluting harmful agents, carrying specific antibodies against infectious agents, and providing a means for their removal. b. Connective tissue - the mucin here forms part of the ground substance between the cells ( fibroblasts ) producing it. In some circumstances, there appears to be a disturbance in the metabolism of the fibroblasts which produce the mucin and the ground substance takes on a bluish hue in H&E sections. The common example is the mucoid ( myxomatous, myxoid ) degeneration that occurs in the heart valves of middle-aged and older dogs. It occurs primarily in the mitral valve and is responsible for a condition specific for this species called endocardiosis. It is important and results in slowly developing heart failure due to the inability of a heart with swollen misshapen valves to effectively pump blood from the left ventricle out into the systemic circulation. A substantial portion of the blood passes back into the left atrium and compromises the filling of the atrium from the pulmonary vein. This leads to back pressure on the pulmonary capillaries with oedema formation in the lungs. This 20 reduces the oxygenation of blood leading to exercise intolerance and may be heard as moist sounds on auscultation of the lungs. Eventually, this failure of the left side compromises the function of the right side and there is also pooling of blood in the venous system i.e. in the liver.