Chapter 3
General Pathology and the Terminology of Basic Pathology
Elizabeth McInnes
Cerberus Sciences, Thebarton, SA, Australia
Pathology is divided into general pathology, which is the study of the actual processes of disease, and systemic pathology, which is the study of diseases or lesions within a specific body tissue (such as the liver). Toxicological pathology is concerned with the lesions caused by the administration in laboratory animals of new compounds intended for human therapeutic use.
Study personnel will find the language that pathologists use perplexing and esoteric. This is not a reflection on the ability of the study personnel! Although difficult for non-pathologists to understand, the complex language of pathology is used to convey precisely the observations made by the pathologist. In general, necrosis, degeneration and vacuolation are given the suffix ‘-opathy’ (a general term indicating a pathologic necrotic or degenerative condition in a specific organ). This is preceded by the organ name (generally in Greek), indicating the tissue or organ affected. An example is ‘nephropathy’, which indicates necrosis or degeneration in the kidney (‘nephros’). Qualifiers such as distribution, duration, severity and type of cell involved are used to ‘build a diagnosis’; for example, ‘multifocal, chronic, severe nephropathy’.
3.1 Cellular Responses to Insults
Pathology revolves around different types of cell injury. Severe cell injury is not difficult to recognise (Figure 3.1), and cell injury is reversible up to a certain point (Kumar et al., 2010a), but if the damage persists, then the cell undergoes irreversible injury and cell death (necrosis). Causes of cell damage and injury include reduced oxygen supply, oxygen-derived free radicals, physical agents, chemical agents, toxins, infectious agents (e.g. bacteria and viruses), hypersensitivity and immune reactions.
Figure 3.1 Severe cell injury is not difficult to recognise. Here, the pus exuding from this ruminant brain clearly indicates that the tissue is not normal. This is called ‘purulent meningitis’.
Reversible cell damage (degeneration) may be slightly more difficult to recognise at necropsy than necrosis. The principle recognisable features of reversible damage are cell swelling and fatty change, both of which are present in the fatty liver illustrated in Figure 3.2. Swelling of the endoplasmic reticulum and mitochondria, as well as myelin figures (whorled masses) and membrane blebs, are seen in electron microscope photographs of reversible cell damage (Kumar et al., 2010a). Reversible cell injury often involves the accumulation of substances within the cytoplasm of a cell, and is characterised by reduced energy in the cell and cell swelling. Accumulated substances are produced by the body; these include fluid (termed ‘hydropic change’), lipid (fat) (termed ‘lipid’, ‘lipidosis’ or ‘fatty change’; see Figure 3.2) and pigments produced during cellular breakdown (‘wear-and-tear pigments’), such as haemosiderin (a golden-brown product produced when red blood cells are broken down), bile (a greenish-yellow product) and lipofuscin (a golden-brown pigment). Lipofuscin is found in liver cells, cardiac muscle cells, adrenal cortex, testis, ovary and neurons in the brain. Bile pigments (bilirubin), haemosiderin (brown) and melanin (black) are endogenous pigments that can accumulate in cells. Glycogen is present in liver cells, and may accumulate in the kidney and liver in diabetes mellitus. Cholesterol may accumulate in foamy macrophages in the lung. Techniques for distinguishing between the different types of pigment include the use of special stains such as Sudan black B (fat), Schmorl’s and Long Ziehl-Neelsen technique for lipofuscin, PAS with diastate for glycogen, Perl’s Prussian blue for haemosiderin and Masson-Fontana for melanin (see Table 1.1).
Figure 3.2 Yellow fatty change in an enlarged ruminant liver.
Necrosis is easy to recognise at necropsy, generally presenting as a yellow to whitish discolouration of tissues, often with a soft or dry consistency. Necrosis is the death of cells and tissues in an animal that is still alive; the cells will show nuclear breakdown, breakdown of plasma membranes and leakage of cell contents under the light microscope (Golstein and Kroemer, 2007). One of the most dramatic and common causes of necrosis is ischaemic damage, which occurs when the blood supply to an organ or part of an organ is reduced or obstructed. Ischaemia is defined as an incident that prevents delivery of substrates and oxygen to tissues. A localised area of ischaemia is called an ‘infarct’ (Figure 3.3), which generally displays a sharp demarcation between normal and necrotic tissue. In the kidney, infarcts are often wedge-shaped, because this corresponds with the area previously supplied by a single arteriole that has become obstructed.
Figure 3.3 Infarcts (*) in a dog kidney, showing a sharp demarcation between normal (red-brown) tissue and necrotic (yellow) tissue.
There are a number of different types of necrosis. Coagulative necrosis (Figure 3.4) occurs in solid organs such as the liver and kidney and appears pale white with a sharp demarcation between the necrotic tissue and the normal vascularised tissue. Liquefactive necrosis occurs when enzymes cause the breakdown of dead tissue to form a viscous fluid; it is often seen in the brain, where it is called ‘malacia’ (Figure 3.5). Caseous necrosis is generally encountered in tuberculous lesions and involves cheese-like necrotic material (Figure 3.6). Fat necrosis involves fatty tissue becoming hard and often mineralised (calcium accumulates within tissues) due to the release of lipases (often because of pancreatitis), which digest fat; it is often seen in the mesenteric fat tissue (Figure 3.7). Gangrene is a variant of coagulative necrosis; it often involves extremities such as the tail or feet, where it occurs as either wet or dry gangrene – wet gangrene is foul-smelling, soft and red in appearance, while dry gangrene tends to be black (Figure 3.8). Finally, fibrinoid necrosis is a form of necrosis of smooth muscle; it is seen in vasculitis, particularly in beagle pain syndrome (Figure 3.9).
Figure 3.4 Coagulative necrosis (*) in a ruminant kidney.
Figure 3.5 Liquefactive necrosis in a ruminant brain.
Figure 3.6 Caseous necrosis in the centres of ruminant liver abscesses.
Figure 3.7 Fat necrosis in ruminant mesenteric fat tissue.
Figure 3.8 Dry gangrene in the black ear tips of a pig.
Figure 3.9 Fibrinoid necrosis in beagle pain syndrome, showing bright pink material in the blood vessel wall.
Characteristics of necrotic cells include karyorrhesis (fragmentation of the nucleus), karyolysis (dissolution of the nucleus) and pyknosis (nuclear shrinkage). Necrosis involves cell death, so ghost outlines of cells are seen under the light microscope. The body responds to necrosis by producing scars, erosions and ulcerations, and sometimes by abscess formation.
Mineralisation or calcification is the deposition of calcium salts in normal or necrotic tissues. It can be felt at necropsy, as the tissues will be hard and gritty, and it is generally visible as a white deposit. There are two types of calcification: dystrophic, which is local and occurs in dead and dying tissues (in the presence of normal serum calcium levels), and metastatic, which involves calcium deposition in normal tissues and usually reflects a disturbance of calcium metabolism or hypercalcaemia (i.e. an increase in serum calcium levels). Causes of hypercalcaemia include vitamin D toxicity, excess parathyroid hormone and kidney failure. Von Kossa and Alizarin red S special stains may be used to demonstrate mineralisation in tissues.
Apoptosis or programmed cell death (Figure 3.10) is a regulated cell suicide programme (Wyllie, 1997). It is an important process during organ development and provides physiological balance to mitosis. It can only be visualised under the light microscope. It occurs in normal tissue turnover (liver, pancreas), embryogenesis (the destruction of the webs between the digits of the human foetus) and endocrine-dependent tissue atrophy (e.g. prostatic atrophy after castration). Apoptosis is characterised by cell shrinkage, chromatin condensation, cytoplasmic blebs and, finally, phagocytosis of apoptotic bodies by adjacent macrophages. The TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) method was developed to demonstrate breaks in DNA that occur in apoptosis. However, as these breaks may also occur during necrosis, the TUNEL technique does not distinguish between the two processes, and caspase immunohistochemistry (IHC) is now thought to be more accurate than TUNEL in identifying apoptotic cells.
Figure 3.10 Apoptosis (*) in a mouse lymph node, showing cell shrinkage, chromatin condensation, cytoplasmic blebs and phagocytosis of apoptotic bodies by adjacent macrophages.
3.2 Inflammation
Study personnel will be familiar with inflammation, which can range from a mild serous nasal discharge seen in a beagle dog on an inhalation study to severe pneumonia and lung abscessation seen in a rat treated with an anticancer drug. Inflammation is the process that occurs when an animal attempts to remove an injurious agent and to repair the damaged tissue. Pathologists indicate inflammation in various organs and tissues by using the suffix ‘-itis’ after the Greek word for the organ; thus, inflammation in the skin is called ‘dermatitis’ and inflammation in the kidney is called ‘nephritis’. Inflammation is divided into acute and chronic, depending on the time frame. Acute inflammation is the immediate and early response to an injurious agent. The hallmark of acute inflammation is increased vascular permeability and a loss of fluid from the leaky blood vessels, whilst its causes include infection by bacteria, fungi, viruses and parasites, immune reactions, trauma, heat and cold, radiation, oxygen radicals, toxins, enzymes and chemicals (Brooks, 2010b).
The clinical signs of inflammation include red, hot, swollen tissues, pain and loss of function of an organ (Figure 3.11). The three major actions of the exudative phase of acute inflammation are an increase in blood flow, structural changes in the microvasculature that allow plasma proteins and leukocytes to leave the circulation and emigration of the leukocytes (white blood cells, neutrophils) from the microcirculation into the area of injury (Figure 3.12). The main components of an inflammatory exudate include fibrin (a protein-rich secretion), serum and inflammatory cells (particularly neutrophils).
Figure 3.11 Clinical signs of inflammation.
Figure 3.12 Major actions of the exudative phase of acute inflammation.
The cells involved in inflammation are illustrated in Figure 3.13. The most important cells in acute inflammation are the polymorphonuclear leukocytes or neutrophils and macrophages (Kumar et al., 2010a). Neutrophils are granulated white blood cells with segmented, multilobed nuclei (which often have a horseshoe appearance); these move through the endothelium of the blood vessel to the area of inflammation, ingest (phagocytosis) and kill microorganisms and release inflammatory mediators. Chemotaxis is the process whereby inflammatory cells move into an area of inflammation. Exogenous chemotactic stimuli include bacterial products, whilst endogenous stimuli include complement. Complement is a system of more than 20 proteins forming a cascade; each protein becomes activated (generally when antibody binds to antigen) and acts on the next inactive protein in order to convert it to an active form. Ultimately, complement ensures that microbes are converted to a state that makes phagocytosis by macrophages easier (Figure 3.14).
Figure 3.13 Cells involved in inflammation: neutrophils, macrophages, eosinophils, mast cells and basophils.
Figure 3.14 The complement system.
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