Pathology means study of suffering. Pathology is divided into General Pathology and Systemic Pathology. General Pathology deals with the basic reactions of cells and tissues to any abnormal stimuli. Systemic Pathology shows the specific responses to those stimuli and pathological changes in the organs or tissues. Four aspects are to be followed to study the disease process. 1. Its cause (etiology), 2. the mechanisms of its development (pathogenesis), 3. the structural alterations induced in the cells and organs of the body (morphological changes, i.e. gross and histopathological appearance). 4. Functional consequences of the morphological changes (clinical significance).
CELL INJURY AND CELL ADAPTATION
Each cell is in a steady-state by its genetic programming of differentiation and functions. When any abnormal stimulus acts upon the cell, the imbalance occurs in the cell. This leads to the injury of the cell, which can be reversible or irreversible. If the stimulus is minimal or removed after first exposure, the cell injury is reversible and the cell will come to its normal state. If the stimulus is in excess or if it occurs in an already injured cell, the cell injury is irreversible.
CAUSES FOR REVERSIBLE AND IRREVERSIBLE INJURY
- Hypoxia—Loss of blood supply (ischemia) which is occluded by arteriosclerosis or by any thrombi leading to decreased oxygen supply to the cells or organ.
- Physical agents—Mechanical trauma, extremes of temperature, sudden changes in atmospheric pressure, radiation and electric shock.
- Chemical agents—Organic and metallic poisons, insecticides, pesticides, environmental and air pollutants, industrial and occupational hazards, alcohol and narcotic drugs.
- Infectious agents—Bacterial, viral, fungal, protozoal and any parasites.
- Immunologic reactions—Foreign agents or autoantigen-antibody reactions.
- Genetic derangements—Genetic defects causing congenital malformations.
- Nutritional imbalances—Protein calorie deficiencies, or nutritional excess.
CAUSES AND MECHANISMS OF CELL INJURY
There are four common causes for cell injury:
- Hypoxic injury
- Injury induced by free radicals
- Chemical injury
- Viral injury.
The cell organelle of attack in hypoxia is mitochondria in which there is decreased oxidative phosphorylation occurs. This leads to decreased ATP synthesis, causing reversible injury to the cell as cell swelling, lipid deposition. When severe ischemia or continuous decreased oxygen supply to the cell occurs, there is cell death (irreversible injury).
During reversible change there is decreased sodium pump, increased influx of calcium and efflux of potassium ions, increased glycolysis and lipid peroxidation occurs. Hydropic swelling of the cell along with granular, crumpled cytoplasm and pyknotic nucleus are seen macroscopically. Ultrastructural findings are blebs in the plasma membrane, loss of microvilli, swelling of endoplasmic reticulum and clumping of nuclear chromatin.
On irreversible change the cell membrane lysis occurred which leads to cell death.
Free Radical Injury
Free radicals are chemical species that have a single unpaired electron in an outer orbit which is readily combines with any agents and produce injury to the cell. Free radicals are produced by the process of initiation and inactivated by the process of termination.
Free radicals are produced within the cells by 1. absorption of radiant energy (UV-rays, X-rays), 2. endogenously through oxidative reactions that occur during normal metabolic processes and 3. enzymic metabolism of exogenous chemical or drugs.
The O2 derived free radicals are:
- Superoxide O2
- Hydrogen peroxide H2O2
- Hydroxyl ions OH.
Superoxide is generated either directly during autooxidation in mitochondria or enzymatically by cytoplasmic enzymes such as xanthine oxidase, cytochrome P450, and other oxidases.
Hydrogen peroxide (H2O2) is produced either by dismutation of O2. Or directly by oxidases present in peroxisomes.
Hydroxyl (OH) radicals are generated
- by the hydrolysis of water caused by ionizing radiation,
- by interaction with transition metals in Fenton reaction,
- through Heber Weiss reaction,
Termination: In this process the free radical reactions are inactivated.
- by the action of endogenous or exogenous antioxidants
- by the action of enzymes
- Superoxide dismutase (SOD) enzyme converts superoxide to hydrogen peroxide,
- Catalase present in peroxisomes decomposes H2O2
- Glutathione peroxidase which catalyses the ability of reduced glutathione (GSH)
Examples of Free Radical Injury
- Chemical injury
- Microbial killing
- Irradiation injury
- O2 and other gases toxicity
In carbon tetrachloride poisoning the free radical formed is CCl3.
This free radical causes lipid peroxidation in the liver hepatocytes, and form fatty change liver as reversible injury and complete cell necrosis as irreversible injury.
The viruses enter into the body and get attached with the host DNA. Thus, it transfers the material in the host cell and change cell as viral coded DNA. This causes to replicate in the body as viral genome-reversible injury. As irreversible injury there is various reactions-cytopathic effect, inclusion bodies as intracytoplasmic or intranuclear or both, giant cell formation.
CELL ADAPTIVE CHANGES
- Fatty change
- Hyperplasia, hypertrophy
Necrosis is the sum of the morphological changes that follow after cell death in a living tissue or organ.
Two essential processes that bring about the changes of necrosis 1. enzymic digestion of the cell and 2. denaturation of proteins.
Types of Necrosis
- Coagulation necrosis
- Liquefaction necrosis
- Fat necrosis
- Caseous necrosis
- Gangrenous necrosis.
This is characterized by conversion of the cell to an acidophilic, opaque tombstone.
Cause: Severe ischemia, e.g. myocardial infarction.
Organ affected: Kidney, heart, adrenal glands.
Pathogenesis: Degeneration of structural and enzymic proteins which blocks the proteolysis of the cell.
Organ affected: Brain.
Pathogenesis: By the action of powerful hydrolytic enzyme hydrolases and favor the denaturation of proteins.
Morphological feature: The solid substance of brain is changed into a cystic structure within 72 hours after death.
Cause: Trauma, inflammation, e.g. acute pancreatitis.
Organs affected: Pancreas, breast, fat depots of abdomen.
Pathogenesis: Due to the action of lipases, triglycerides are decomposed and produce free fatty acids. Free fatty acid complex with calcium ions to form calcium soaps.
Morphological features: The necrotic foci appear opaque and chalky white areas. Histologically, the necrosis takes the form of foci of shadowy outlines of necrotic fat cells surrounded by inflammatory reaction.
Cause: Mycobacterium tuberculosis.
Pathogenesis: Combination of coagulative necrosis and liquefactive necrosis.
Morphological features: Caseous necrosis is soft, friable, whitish gray debris resembling clumped cheesy material. Microscopically, amorphous granular debris enclosed within a granulomatous inflammatory wall.
Cause: Ischemia with overwhelming putrefactive bacterial action.
Organ affected: Lower limbs.
Pathogenesis: When coagulative pattern is dominant, the process is termed dry gangrene. When liquefactive action is dominant, it is designated as wet gangrene.
Abnormal accumulation of fat within the parenchymal cells is known as fatty change or fatty infiltration.
- Excess alcoholism
- Diabetes mellitus
- Protein malnutrition
- Excessive entry of free fatty acids into the liver
- Enhanced fatty acid synthesis
- Decreased fatty acid oxidation
- Increased esterification of fatty acids to triglycerides due to increase in a glycerophosphate enzyme in mitochondria
- Decreased apoprotein synthesis
- Impaired lipoprotein secretion from the liver.
Morphology: Liver is enlarged, yellowish greesy organ, weighing 3 to 5 kg, soft in consistency.
Histologically, fatty change is seen hepatocytes as large cells with clear cytoplasm and peripherally pushed flat nucleus.
Heart: Tigered effect or thrush breast appearance, i.e. bands of dark red brown, uninvolved myocardium alternating with yellowish affected myocardium.
Stains used to demonstrate the fat:
- Hematoxylin and eosin stain, Frozen sections
- Sudan IV, Oil Red O—Orange red color
- Fluorescent—Acridine Orange.
Hyperplasia and Hypertrophy
Increase in the cell thickness and increase in size of organ. This is either physiological or pathological.
Physiological: The common cause is due to hormonal, example, uterine enlargement during pregnancy and increase thickness of endometrium during menstrual cycle.
Pathological: In cancerous lesions there is increase cell layers and increase in organ size.
It is defined as change of one adult parenchymatous cell type into another adult parenchymatous cell type. This is not precancerous lesion.
In chronic smokers the stratified ciliated columnar cell lining of nasal tube is changed into squamous epithelium.
In alcoholics the stratified squamous epithelial lining of esophagus is changed into columnar epithelium.
This is increase in cell thickness with alteration in nuclear cytoplasmic ratio. The normal nuclear cytoplasmic ratio is 1:4 or 1:6. In dysplasia the nuclear cytoplasmic ratio is 1:1. This is precancerous lesion. Dysplasia is identified as mild, moderate and severe dysplasia according to the involvement of cell layers by PaP smear or in biopsy. In cervical smears which are taken by using Ayre's spatula and stained by Papanicolaou stain, dysplasias are classified as:
CIN I: Mild Dysplasia—Koilocytic change with mild variation in nuclear cytoplasmic ratio involving 1/3rd of cell layer.
Cin II: Moderate Dysplasia—Change involving 2/3rd of cell layer.
Cin III: Severe Dysplasia—Change involving all the three layers.
Carcinoma in situ—Change involves all the three layers including basal layer not crossing the basement membrane.
Shrinkage in organ size due to decrease in cell thickness causes;
- Prolonged period of immobilization
- Loss of innervation
- Loss of blood supply
- Genetic factors.
Calcification is defined as pathological deposition of calcium in the tissues in living body. This is classified into two types: dystrophic and metastatic calcification.
In this type of calcification there is no increase in serum calcium level, no alteration in calcium metabolism but deposition of calcium in the ulcerative or necrotic tissues. Example: calcium is deposited in the stenosed mitral valves, ulcerative plaques of atherosclerosis, necrosed areas.
This occurs in two processes:
In initiation process, the calcium is mobilized from the serum and changed into hydroxyl apatite molecules which is a transport molecule of bone calcium. In propagation process, the molecules are deposited in tissues, intracytoplasmic, intranuclear or in both locations. Histologically, the calcium is deposited as vesicles or in concentric rings.
Here, the calcium is deposited in normal tissues. This is associated with abnormal calcium metabolism, increased serum calcium level (calcemia).
Example: Milk alkali syndrome, hyperparathyroidism, secondaries in bone marrow, leukemias and conditions which causes the bone marrow depletion.