Several diseases involve abnormalities of tissue growth. These vary from congenital defects in organ development, to neoplasia. Throughout the embryonic and postnatal development of an individual, tissues grow mainly due to the process of cell proliferation. Admittedly, tissue mass also can be increased by an increase in cell size, but as a component of growth, this mechanism is unimportant. Many tissues retain the capacity for cellular proliferation throughout the life of the individual. In some, there is continual mitotic division to replace cells that are lost. In the skin, for instance, there is continual loss of keratinised epithelial cells requiring replacement by proliferation of basal cells. Similarly in the bone marrow there is continual cell proliferation to replace cells of the peripheral blood whose lifetime is limited. Other cells, such as those of the renal tubular epithelium or of the liver, are not continually proliferating. However, they retain the capacity for mitotic division as a mechanism for repair.
Most of the daughter cells that result from cell proliferation undergo differentiation, adopting the structural and functional characteristics of the tissue they are destined to become. Thus, cells committed to be epidermal cells only reproduce epidermal cells, liver cells produce liver cells, and so on. Usually, fully differentiated cells lose the capacity to divide so that loss of this capacity may be regarded as one feature of the process of differentiation.
THE CELL CYCLE
Most tissues can be regarded as containing a mixture of cells. Some cells are continually dividing, while others are not dividing but can return to the mitotic pool. Still, some component cells are terminally differentiated and no longer able to undergo mitosis. The sequence of events comprising mitosis is called the CELL CYCLE.
The cycle consists of four stages. Cell division occurs during the M phase. In the S phase, synthesis of DNA occurs. Daughter cells may undergo differentiation and no longer capable of division, or they may enter G0. Cells in G0 are mitotically inactive but may be recalled to the growth fraction under appropriate conditions. G1 is the most variable phase. The time taken to go through G1 largely decides the length of the cycle and therefore the rate of cell proliferation. During the S phase of the mitotic cycle, DNA and chromosomal proteins are synthesised. Proliferating cells must synthesize all their other components to avoid a progressive reduction in size during mitotic division.
Figure 14. The Cell Cycle
It is also important to realise that the rate of proliferation of cells is not the only determinant of the rate of tissue growth. The rate of tissue growth depends on three factors:
1] The rate of cell proliferation
2] The fraction of cells in the mitotic pool (the growth fraction)
3] The rate of cell loss
In growth, as in all biological phenomena, there is variation between normal individuals. However, when outside the normal range, these variations may be regarded as pathologic and may result in functional abnormalities that we recognise as disease. Disturbances of growth may result in an excess or a deficit of tissue, or may produce an abnormal pattern of development.
Malformations may occur during the growth and development of a tissue or organ and are present at birth as congenital lesions. Although they may be due to genetic defects, they may also be caused by a variety of factors (toxic, infectious, etc.). Isolated cases of developmental anomalies therefore cannot be assumed to be inherited. The congenital anomalies reported in domestic animal species may be too many to be listed here, and will be dealt with later in the course. Their effect on the animal varies from negligible to lethal. Certain types of developmental abnormalities can be conceptualised more easily as abnormalities of growth, and these include AGENESIS, APLASIA, and HYPOPLASIA.
Agenesis of an organ or tissue suggests a complete failure of that tissue to develop. Aplasia suggests a failure to grow and therefore implies the presence of a rudimentary organ. The clinical significance depends on the organ involved. Example, aplasia of one kidney would be expected to be clinically not apparent, whereas bilateral aplasia of kidneys would be lethal. The term aplasia also is used to refer to failure of a tissue to renew itself (e.g., the term aplastic anaemia).
Hypoplasia refers to the failure of an organ to reach normal size. It is therefore a developmental defect occupying the spectrum between aplasia and normal development. Examples regularly seen are renal hypoplasia and testicular hypoplasia. Hypoplasia of an organ may cause clinical disease, and its severity depends on the organ affected, and the degree to which function is reduced.
Some lesions included under growth abnormalities may be regarded as adaptive responses of cells to changes in the demand made upon them. These include the following:
Atrophy implies an acquired change in a previously normal tissue and is the subsequent decrease in the size of an organ or tissue. The reduction in size may be due to a decrease in the number of cells (numerical atrophy) or the size of the individual cells (quantitative atrophy), or both. The loss of cell is by apoptosis. This type of lesion must be differentiated from agenesis and hypoplasia. Atrophy can occur under physiological or pathological conditions.
Physiological atrophy occurs in many tissues as a normal manifestation (e.g., atrophy of the thymus, mammary gland in males, involution of the uterus post-partum, and involution of fetal structures after birth like the ductus arteriosus, and umbilical vessels). Pathological atrophy includes the following types:
1] Nutritional atrophy - due to inadequate
dietary intake, or in events of starvation;
2] Vascular atrophy - due to ischaemia;
3] Disuse atrophy - due to reduced functional activity (e.g., paralysed limb)
4] Pressure atrophy - probably mediates through vascular insufficiency due to long standing pressure (e.g., by tumour growth, surgical cast)
5] Endocrine atrophy - due to loss of stimulation from trophic hormones (e.g., pituitary cyst leading to generalised somatic atrophy)
6] Atrophy due to:
a) Metabolic diseases
The differing types listed above are based on clinical varieties, but the basic aetiology is a deprivation of blood supply or nutritional requirements to the tissue with resultant atrophy. Grossly, the tissues or organs are smaller than normal but usually retain their normal shape. Microscopically, there are fewer cells than normal and these cells are smaller than normal. The tissue, however, appears more cellular due to the diminished amount of cytoplasm surrounding the remaining nuclei.
HYPERTROPHY and HYPERPLASIA
Hypertrophy is the increase in the size of the tissues or organ due to an increase in the size of individual cells. In pure form, hypertrophy occurs only in muscle and is usually a response to an increased demand for work. Hyperplasia is an increase in tissue mass or organ size due to an increase in the number of constituent cells. Frequently, these two changes occur simultaneously in the tissues, but hypertrophy occurs alone in those tissues that are incapable of regeneration (e.g., cardiac muscle: See lecture notes on Inflammation and Healing). Both processes may be physiological or pathological, and the main factors are work load or endocrine stimulation. Types include the following:
1] Endocrine - e.g., mammary gland
2] Compensatory - e.g., when one kidney is hypoplastic or surgically removed
3] Functional - e.g., muscles in response to heavy exercise; left ventricular myocardium following narrowing of aortic valve (aortic stenosis)
4] Replacement - as part of the repair process (e.g., healing of fractured bone, healing of liver defect by regeneration)
5] Reactive - e.g., reactive hyperplasia of lymphoid tissues and bone marrow in response to infection or anaemia; Also in response to chronic irritation e.g., thickening of the skin in mange mite infestation.
6] Neoplastic - tumours are formed because of localised areas of increase in cell number (See under Neoplasia)
Usually, there is no well-defined cut off between physiologic and pathologic response. A response that at one level may be considered physiologic may be considered pathologic when it exceeds some arbitrarily selected limits.
Patterns of hyperplasia include the following:
1] Nodular hyperplasia - where the
added tissue masses assume nodules e.g., in liver tissue remodeling
2] Cystic hyperplasia - form spaces lined with epithelia e.g., cystic prostatic hyperplasia
3] Papillary hyperplasia - form frond like projections e.g., hyperplasia of lining epithelia of tubular organs
4] Adenomatous hyperplasia - form gland-like mass resembling neoplasm
Metaplasia is an adaptive response in which
a different but related type replaces one type of mature differentiated
cell. It is usually reversible and is most commonly seen from more specialised
to less specialised but more resistant cell type (e.g., columnar or transitional
cell type to squamous epithelia).
Epithelial metaplasia occurs following prolonged irritation or chronic infection (e.g., stones in urinary bladder), and in nutritional deficiencies (e.g., Vitamin A deficiency cause squamous cell metaplasia of prostate gland). Connective tissue metaplasia on the one hand, occur in association with repair processes (e.g., Fibroblast retains their mesenchymal ability to change into other connective tissue cells - may form bone, cartilage, or fibrocartilage).
Metaplasia does not occur because of alterations
in existing mature cells. Rather it depends on proliferation of germinal
cells whose progenies undergo modified differentiation. The change often
is associated with hyperplasia and is usually orderly. Loss of orderly
arrangements leads to dysplasia.
Dysplasia literally means "abnormal growth".
However, it is used in a more restricted sense to describe a proliferative
response accompanied by loss of regular differentiation and by cellular
atypia and disorderliness. Thus, it may be thought of as disorderly or
atypical hyperplasia. These changes most frequently are observed in epithelia
subjected to chronic irritation or inflammation. Cellular atypia is characterised
by PLEOMORPHISM (variation in size and shape) and HYPERCHROMICITY (increased
staining). There is a loss of the normal regular progression from germinal
to fully differentiated cells and mitosis is found in abnormal positions.
Dysplasia is however reversible if the cause is removed. Yet, when left
alone, dysplasia may progress to become neoplasms.