Introduction to Pathology

Introduction to Pathology

• Pathology studies the causes and effects of disease and associated changes at the cellular, tissue, and organ levels
• Etiology refers to the origin of a disease, encompassing underlying causes and modifying factors
• The causes of common diseases are a combination of genetic susceptibility and environmental triggers
• An understanding of genetic and environmental factors is a key aspect of medicine now
• Pathogenesis comprises the sequence of events during disease development, that describes how etiological factors trigger cellular/molecular changes, ending in the specific structural/functional abnormalities characterizing disease
• Knowing disease etiology and pathogenesis is important to develop well-founded treatments
• Pathology explains the causes and development of disease that represents the scientific basis of medical practice
• Pathologists identify changes in the macroscopic/microscopic appearances (morphology) of cells/tissues and biochemical alterations in body fluids to make diagnoses and guide treatment
• Morphological, molecular, microbiological, and immunological techniques are used to define biochemical, structural and functional changes occurring in cells/tissues/organs in response to injury
• Traditionally, the discipline is divided into general and systemic pathology
• An initial focus is put on cellular/tissue alterations caused by stimuli in most tissues, while a secondary analysis is performed on reactions and alterations in specialized organs

General Vision of Cellular Responses to Stress and to Harmful Stimuli

• Cells actively participate in their environment, adjusting structure/function to accommodate changing demands and various types of extracellular stress
• Cells maintain their intracellular environment within a narrow range of parameters, maintaining homeostasis
• When cells encounter stresses or pathological stimuli, they undergo adaptation to achieve a new equilibrium that preserves viability and function
• Hypertrophy, hyperplasia, atrophy, and metaplasia are the main adaptive responses
• Cellular injury occurs if the adaptive capacity is exceeded or if external stress is harmful
• The lesion is reversible within certain limits, with cells returning to their basal state, and exposure to intense/persistent stress leads to irreversible injuries and cell death
• Cell death is a crucial event in the evolution of disease in any tissue/organ
• Ischemia (lack of blood flow), infections, toxins and immune reactions can cause cell death
• Cell death is normal and essential during embryogenesis and organ development and homeostasis
• Relationships between normal, adapted, reversibly/irreversibly injured cells are illustrated by responses of the heart to different stresses
• The myocardium (heart muscle) adapts through hypertrophy to generate the required contractile force when subjected to a persistent load or in the presence of a stenotic valve
• Myocardial cells may be injured if increased demand is not relieved or blood flow decreases due to an occluded coronary artery (ischemia)
• Myocardial injury can be reversible if stress is mild or the arterial occlusion is incomplete/brief, it can be irreversible (infarction) after complete/prolonged occlusion
• Types of stress and injury affect the morphology and functional status of cells and tissues
• Cardiomyocytes (cardiac muscle cells) suffer non-contractility temporarily, thus even a mild injury leads to a lethal clinical impact
• Whether the specific stress adaptation or reversible/irreversible injury occurs depends on, cellular metabolism, blood supply, and nutritional status
• How cells adapt to stress, the acute cell damage, the causes, and consequences are discussed
• Reversible cell injury, subcellular alterations, cell death, intracellular accumulations, pathological calcification, and cellular aging are also mentioned

Adaptations to Cellular Stress

• Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to environmental changes
• Physiological adaptations usually represent cell responses to stimulation by hormones or endogenous substances (hormonal induction)
• Pathological adaptations are responses to stress that allow cells to modulate structure and function to avoid cell injury
• Hipertrophy (increasing cell size) is a type of adaptation, as well as hyperplasia (increase cell numbers)

Hipertrophy

• Hipertrophy is an increase in cell size that results in an increase in the size of the organ
• This differs from hyperplasia, in which there is an increase in cell number due to proliferation
• Hypertrophy does not involve new cells; cells are larger and contain more structural proteins and organelles
• Hyperplasia is an adaptive response of replicative cells, while hypertrophy occurs when cell division is limited
• Hypertrophy and hyperplasia can coexist, leading to an overall enlarged organ (hypertrophic)
• Hypertrophy can be physiological or pathological and caused by increased functional demand or stimulation from growth factors or hormones
• The massive increase in the size of the uterus during gestation results from hypertrophy and hyperplasia of smooth muscle, stimulated by estrogen
• Striated muscle cells in the heart or skeletal muscle only undergo hypertrophy when subjected to increased demand due to limited division
• Bodybuilding is due to hypertrophy of skeletal muscles
• An example of pathological cellular hypertrophy is the increase in heart size as a result of hypertension or aortic valve disease
• Mechanistic forces implicated in cardiac hypertrophy involve mechanical stimuli, such as stretching, and trophic stimuli, like growth factors and adrenergic hormones
• These stimuli trigger signaling pathways, which culminate in gene induction and stimulating synthesis of more cellular proteins (growth and structural factors)
• Cells are able to generate more force per contraction
• Furthermore, changes in contractile proteins can be observed, from the adult forms to the fetal/neonatal ones
• The heavy chain of myosin a is replaced by the form B in muscle hypertrophy, allowing for slower contraction from an energetic viewpoint
• There is a limit to the hypertrophy mechanisms, and structural/functional deterioration can occur once that limit is surpassed, with the enlargement of the muscle mass then ceases to compensate for overload
• Fragmentation and loss of contractile myofibrillar elements can happen, due to the finite limits in vasculature, adequate mitochondrial supply of ATP, and biosynthetic machinery
• Ventricular dilation and heart failure are the net result of these changes
• Adaptations to stress can progress to functionally significant cellular lesions if stress is not relieved

Hyperplasia

• Hyperplasia occurs if the cell population can replicate
• It can occur with hypertrophy in response to the same stimuli
• Hyperplasia can be physiological or pathological
• They are stimulated by growth factors synthesized by different cells
• The two types of physiological hyperplasia are hormonal hyperplasia and compensatory hyperplasia
• Hormonal hyperplasia is exemplified by the proliferation of the glandular epithelium of the female breast during puberty and pregnancy
• Compensatory hyperplasia occurs when a portion of the tissue is eliminated or diseased
• Mitotic activity in remaining liver cells begins after 12 hours following partial resection of the liver, restoring normal liver weight
• Liver is stimulated by polypeptide growth factors produced by the hepatocytes, as well as by non-parenchymal liver cells
• Growth inhibitors disconnect cell proliferation after restoration of hepatic mass
• Hormonal factors of growth cause the most forms of pathological hyperplasia via excessive stimulation
• Epithelial proliferation is tightly regulated after a normal menstrual period, stimulated by pituitary hormones/ovarian estrogens and inhibited by progesterone
• Endometrial hyperplasia results from the alteration of the balance between estrogen and progesterone, causing abnormal menstrual bleeding
• Proliferating fibroblasts/blood vessels help repair tissue within wound healing(v. chapter 2) via proliferative rates and released growth factors
• Mitogenic factors are produced by leukocytes or genes encoded by the viral genes (or by genes of the infected host cells) upon lesion
• Hyperplastic process stays controlled; if the hormonal/growth-factor stimulation abates, the hyperplasia disappears
• Benign pathological hyperplasias differs from cancer because of its normal regulatory mechanisms
• Pathological hyperplasia constitutes a fertile ground for cancer development
• People with endometrial hyperplasia have a higher risk of developing endometrial cancer
• Certain infections by papillomavirus predispose to cervical cancers

Atrophy

• Atrophy is the reduction in cell size due to loss of cell substance
• The entire tissue or organ decreases in size when sufficient number of cells are affected, with cells having diminished function but not being dead however
• Causes of atrophy are a decrease in workload, loss of innervation, reduced irrigation, inadequate nutrition, and loss of endocrine stimulation or aging (senile atrophy)
• Some of these stimuli are physiological or pathological
• The fundamental cellular changes are identical, with cell withdrawals at sizes in which survival is possible
• New equilibrium via diminished irrigation, nutrition, or trophic influence is achieved
• Atrophy results from decreased protein synthesis and increased protein degradation in cells
• Protein declines because of reduced metabolic activity
• Ubiquitin-proteasome pathways mostly degrade proteins, which are linked to proteins targeted for degradation in proteosomes
• This is seen in various catabolic states, such as cancer
• Autophagy (self-eating) with greater number of autophagic vacuoles accompanies atrophy in many situations
• Cells eat their own components to find nutrients and survive, a process to be defined later

Metaplasia

• Metaplasia is a reversible change in which one type of adult cell (epithelial or mesenchymal) is substituted by another type of adult cell
• In this cellular adaptation, cells sensitive to a particular stress are replaced by other cell types with a greater capacity to withstand the adverse environment
• Metaplasia occurs as a result of reprogramming of stem cells
• Epithelial metaplasia is exemplified by squamous change in the respiratory epithelium of habitual smokers.
• Normal columnar ciliated epithelial cells in the trachea/bronchi are focally or widely replaced by stratified squamous epithelial cells
• The transformed epithelium can survive circumstances the more fragile specialized epithelium wouldn't tolerate
• Although metaplastic squamous epithelium has survival advantages, important protective mechanisms are lost
• Epithelial metaplasia is a double-edged sword; Influences inducing metaplastic transformation can predispose to malignant transformation of the epithelium
• Squamous metaplasia of the respiratory epithelium frequently coexists with cancers composed of malignant squamous cells
• Smoking causes squamous metaplasia and cancers arise in some of these altered foci later
• Deficiency can induce squamous metaplasia of the respiratory epithelium, due to vitamin A being essential for normal epithelial differentiation
• Metaplasia doesn't always imply a change of columnar epithelium by a squamous one; During chronical gastric reflux, the distal esophageal epithelium can suffer a metaplastic columnar transformation
• Metaplasia can affect mesenchymal cells, but, in this case, it is usually a response to some pathological alteration and not an adaptive response to stress
• Bone sometimes forms in soft tissues on centers of lesion