Introduction to Pathology Pathology: Literally translated, pathology is the study (logos) of disease (pathos, suffering). It involves the investigation of the causes of disease and the associated changes (structural and functional) at the levels of cells, tissues, and organs, which in turn give rise to the presenting signs and symptoms of the patient. Lesions: Lesions are the characteristic changes in cells and tissues produced by disease in an individual or experimental animal. Pathogenesis: Pathogenesis (i.e. how of disease) is the sequence of events in the response of cells and tissues to an injurious agent (pathogen) starting from the initial stimulation to the ultimate expression of the disease. It is also defined as the step by step developmental process (sequence of events) from the beginning of the disease to its termination. Diagnosis: Diagnosis (i.e. what is wrong) is the process of determining which disease or condition explains a person's symptoms and signs. Etiology: The term etiology (i.e. why of disease) refers to the science that deals with the causes or origin of the disease or the factors that produce or predispose toward a certain disease or disorder. Cell injury Adaptation and cell injury: In normal conditions, the cells of the body are in equilibrium with their external environment. They maintain their internal machinery in a dynamically stable and steady state called homeostasis. When this homeostasis is disrupted by external disturbances (stress), changes within the cells occur to counteract the external disturbances. In other words the cells are able to handle normal 1
(physiological) and sometimes, abnormal (pathological) demands without getting injured. To achieve this there will be a number of changes, inside the cells, in which a new altered steady state is created. These induced changes are referred to as adaptations. The aim of the adaptations is to prevent cell injury, i.e., preserve the viability of cells and tissues during their exposure to a stress. Examples of adaptations 1. Hypertrophy of skeletal muscles due to an increase in the size of the individual muscle fibers as in athletes (sport individuals) or heavy mechanical workers. 2. Atrophy in which there is a decrease in the size and function of cells and consequently the size of the organ or tissue containing them. If the external disturbance (injurious agent or stress) persists or when no adaptive response is possible (sudden severe injurious agent, leaving no time for adaptive responses to take place), a sequence of events follows that are collectively known as cell injury. Causes of cell injury A. Genetic causes A genetic disorder or disease is a condition caused by abnormalities in genes or chromosomes. The term genetic diseases, most commonly, refers to diseases present in all cells of the body and present since conception (fertilization of the ovum). B. Acquired causes 1. Nutritional imbalances a. Deficiencies such as deficiency of proteins, vitamins and elements essential for specific metabolic processes. b. Excesses such as excess of lipids and carbohydrates. 2. Hypoxia The term hypoxia refers to a decrease in oxygen supply to the cells. It leads to cessation of the oxidative respiration of the cells. Hypoxia usually results from: a. Ischemia (loss of blood supply) which is the most common cause and occurs when the arterial blood flow is interfered due to narrowing of the lumen. 2
b. Inadequate blood oxygenation due to cardiac failure and/or respiratory failure. c. Decrease in the oxygen-carrying capacity of the blood due to anemia and carbon monooxide poisoning. 3. Physical factors such as trauma (mechanical injury), extreme heat, deep cold, electricity and radiation. 4. Chemical factors such as: Strong acids and alkalis, poisons (arsenic or cyanide), insecticides, etc. 5. Infectious agents including viruses, bacteria, fungi and parasites. 6. Immunological factors e.g. hypersensitivity reactions triggered by drugs (e.g., penicillin) and immunological reactions directed to self-antigens (autoimmune diseases). 7. Endocrine factors e.g., excessive or deficient hormonal activity. Mechanisms of cell injury Injurious agents induce cell injury by affecting on one or more of the following cellular targets 1. The cell membranes, e.g., bacteria of gas gangrene elaborate phospholipid hydrolysis enzymes (phospholipases), which attack the phospholipids in cell membranes. 2. Aerobic respiration that is responsible for ATP production. For e.g., cyanide inactivates the cellular enzyme cytochrome oxidase and thus leading to cell asphyxia. 3. Synthesis of enzymes and structural proteins. 4. The genetic apparatus. Factors influencing the severity of cell injury 1. Type, duration and severity of the injurious agent. 2. Type of the affected cells: a. The neurons are highly susceptible to ischemic damage. They undergo irreversible damage when deprived of oxygen (by ischemia) for 3 to 4 minutes. b. Myocardial cells and hepatocytes are of intermediate susceptibility to ischemic damage (20-30 minutes). c. Skeletal muscles, the epidermis of the skin and fibroblasts are of low susceptibility to ischemia (many hours). 3
Types of Cell Injury Cell injury is divided into: Reversible cell injury Irreversible cell injury Reversible cell injury It is a type of cell injury in which the pathological changes will regress and disappear when the injurious agent is removed and the cells will return to normal morphological and functional state. Mechanism of ischemia-induced reversible cell injury 1. Ischemia leads to hypoxia, and this in turn results in reduction of the available ATP. 2. The cell, as a result of hypoxia, switches over to anaerobic glycolysis, therefore, the glycogen stores get depleted with an increase in the concentration of the intracellular lactic acid. 3. The lack of ATP results in failure of sodium-potassium pump which leads to influx of the sodium into the cell and this is accompanied by accumulation of water. The result is swelling of the cell. 4. Additionally the lowering of the intracellular ph (by the lactic acid) interferes with the proper functions of the intracellular enzymes. Irreversible cell injury It is a type of cell injury which occurs when the injurious agent persists or when it is severe from the beginning. In this case, the cell reaches the maximum limit of its ability to adapt and then it will be pushed into the injurious phase. At first the injury is reversible, but later it reaches the point where it becomes irreversible. Point of no return It is the precise moment of transition from reversible to irreversible cell injury. At this point, no adaptation can save the cell and the progression to cell death is inevitable (unavoidable). 4
Mechanism of irreversible cell injury (cellular alterations seen in irreversible cell injury): 1. Extensive damage to the plasma membranes. 2. Vacuolization of the mitochondria. 3. The lysosomes leak their hydrolytic enzymes into the cytoplasm. Activation of these enzymes leads to enzymatic digestion of cell components. 4. The point of no return is reached when the cell nucleus is damaged beyond repair. 5. Following cell death, there is leakage of the lysosomal enzymes into the extracellular space resulting in degradation of the extracellular matrix. 6. This is followed by phagocytosis of the dead cells or calcification of the dead tissue. Patterns of reversible (sub-lethal) cell injury If the injury is not severe enough to kill the cell, the cell exhibit various morphological changes. These changes are considered reversible and are classically called degenerative changes. Note: The term Degeneration means deterioration, i.e., change from a higher to a lower form, especially change of tissue to a lower or less functionally active form. The reversible (sub-lethal) cell injuries include the following patterns of morphological changes: i. Intracellular and extracellular accumulation ii. Intracellular and extracellular pigmentation Intracellular and extracellular accumulation Sub-lethal injuries or disease processes sometimes cause accumulation of altered metabolic products within the cytoplasm of cells and within the extracellular spaces. The accumulation includes: 1. Water (Cellular swelling) 2. Triglycerides (Fatty change) 5
3. Protein (Hyaline change and amyloidosis) 4. Glycogen (Glycogen degeneration) 5. Mucopolysaccharide (Mucoid Degeneration). 1. Cellular swelling (Cloudy swelling) It is an early pathological change characterized by accumulation of water within the cytoplasm of the affected cells. It can be seen in many examples of reversible cell injury. The extra-fluid may be seen by light microscopy as an increase in the size of the cell with pallor of the cytoplasm (cloudy swelling). 2. Hydropic degeneration This term is used to describe a more severe condition of cellular swelling characterized by formation of clear vacuoles within the cytoplasm of the affected cells due to continuous accumulation of water. 3. Fatty change (Fatty degeneration) This term refers to abnormal accumulation of fat within the cytoplasm of parenchymal cells such as those of the liver, kidney and heart. It is an example of reversible (non-lethal) cell injury and is often seen in the liver because of the central role of this organ in fat metabolism. Gross features of fatty degeneration In the liver, mild fatty change shows no gross changes, but with progressive accumulation, the organ enlarges and become increasingly yellow, soft and greasy to touch. 4. Hyaline change The term hyalin usually refers to an alteration within cells or in the extracellular space, which gives a homogeneous, glassy, pink appearance in routine stained histological sections. Hyaline change is almost always associated with the accumulation of a protein in the tissue either intracellularly (intracellular hyalin) or exracellularly (extracellular hyalin). Note: The term routine-stained histological sections means hematoxylin and eosin stained histological sections (H and E stained histological sections). 6
Examples of intracellular hyalin a. Re-absorption protein droplets (tubular epithelial hyaline droplets) seen within the cytoplasm of the lining epithelial cells of the renal tubules in cases of protein losing nephropathies such as the nephrotic syndrome. In such conditions, the lining epithelial cells of the renal tubules try to re-absorb the excessive quantities of the proteins that had leaked through the glomerular filtrate. b. Mallory body (Alcoholic hyalin or Mallory's hyalin) The term Mallory body refers to a homogenous, eosinophilic inclusion with a characteristic twisted-rope appearance found in the cytoplasm of liver cells. The Mallory bodies are classically found in liver cells of people suffering from alcoholic liver disease and they were thought to be specific for this disease, however, they are also recognized in other pathological conditions such as primary biliary cirrhosis, morbid (pathologic) obesity and hepatocellular carcinoma. b. Examples of extracellular hyalin 1. Collagenous fibrous tissue in old scars may appear hyalinized (give a homogeneous, glassy, pink appearance in H and E stained histological sections), but the physiochemical mechanism underlying this change is not clear. 2. In long-standing hypertension and diabetes mellitus, the walls of arterioles, especially in the kidney, become hyalinized, due to deposition of extravasated plasma protein. 5. Amyloidosis: Amyloidosis is an inherited or acquired pathological lesion and it refers to a variety of conditions in which amyloid proteins are extracellularly accumulated in tissue or organ. In routine H and E stained-stained histological sections, the amyloid proteins appear as amorphous, homogenous, eosinophilic, material aggregated extracellularly within the affected tissue or organ. 6. Glycogen accumulation It is an accumulation of glycogen (which appears as clear cytoplasmic vacuoles) within the cytoplasm of affected cells particularly the parenchymal cells of the liver and kidney, the leukocytes, and the myocardial and skeletal muscle fibers. It occurs in: 7
a. Prolonged hyperglycemia, particularly in diabetes mellitus which causes glycogen accumulation within the cells of the liver and heart, the epithelial cells of distal renal tubules and cells of the Langerhans islet within the pancreas. b. Glycogen storage disease: A genetically determined disease associated with absence of an enzyme required to metabolize the carbohydrates. c. hyperadrenocorticism. d. Steroid induced hepatopathy. 7. Mucoid Degeneration (Mucopolysaccharidosis) Mucoid degeneration is the degeneration of connective tissue into a gelatinous or mucoid-like substance due to extracellular accumulation of mucopolysaccharide. It is seen in some specific conditions such as: a. Endocardiosis, a degenerative, sometimes senile condition of the heart valves. b. It is also seen in the dermis of the skin in cases of hypothyroidism, causing the manifest wrinkling of the skin particularly of the human face creating the tragic appearance typically associated with such a condition. 8