1. Lecture 46: Cellular adaptation
Objectives
This lecture provides an understanding of
This lecture provides an understanding of various cellular adaptation in terms of the terminologies used, mechanism, morphology and specific examples
Learning outcomes
At the end of the lecture ,student will be able to
Define the terms atrophy, hyperplasia, metaplasia, hypertrophy and dysplasia
Discuss pathological and physiological causes ,mechanism and morphology of atrophy
Discuss pathological and physiological causes ,mechanism and morphology of metaplasia
Discuss pathological and physiological causes ,mechanism and morphology of hyperplasia
Discuss pathological and physiological causes ,mechanism and morphology of hypertrophy
Describe the histological changes denoting dysplasia

2. ADAPTATION
physiological ability (reserve mechanism) in response to prolonged (excessive) exposure to stress agents (stimuli)
The response ;
Metabolic modification
Structural adaptation (change in growth pattern)

4. CELL CYCLE Basic knowledge : growth potentiality of cells
Cell types – labile, stable , permanent cells
CELL CYCLE

6. Excessive growth
Increase demand for work (function) Excessive hormonal stimulation
Hyperplasia Increase in size of an organ as a result of increased number of component cells (labile/stable)
Hypertrophy ; Increase in size of an organ as a result of increased size of individual cells (permanent cells)
A combination of these - Hypertrophy & hyperplasia commonly co-exist and the stimuli are similar.

7. Hyperplasia = Increase in the number of normal cell
Increase in cell number by mitosis
Increase in the size of an organ or tissue caused by an increase in the number of cells composed of labile and stable cells.
Hyperplasia takes place if the cell population is capable of replication
Hyperplasia results when cells of a tissue are stimulated to undergo mitotic division, thereby increasing the number of cells.
In some cases, hyperplasia occurs together with hypertrophy E.g. In pregnancy, uterine enlargement is caused by both hypertrophy and hyperplasia of the smooth muscle cells in the uterus
Increased risk for progressing into dysplasia and cancer, in some cases Example-endometrial hyperplasia

8. Causes of Hyperplasia a. Chronic irritation c.Chemical imbalance
Physiological
(1) Hyperplasia of bone marrow cells producing red blood cells in individuals living at high altitude –stimulated by increased production of the growth factor erythropoietin.
(2)Hyperplasia of breast tissue at puberty, and in pregnancy and lactation, under the influence of several hormones, including oestrogens, progesterone, prolactin, growth hormone and human placental lactogen.
(3) Hypertrophy hyperplasia of uterine smooth muscle at puberty and in pregnancy, stimulated by oestrogen
(4) Thyroid hyperplasia as a consequence of the increased metabolic demands of puberty and pregnancy
a. Chronic irritation
(1) Thickened epidermis from constant scratching
(2) Bronchial mucous gland hyperplasia in smokers and asthmatics
(3) Cirrhosis of the liver due to alcohol excess
b.Hormone stimulation
(1) Acromegaly due to an increase in growth hormone and insulin growth factor-1
(2) Endometrial gland hyperplasia due to hyperestrinism
(3) Benign prostatic hyperplasia due to an increase in dihydrotestosterone
(4) Gynecomastia (male breast tissue) due to increased estrogen
(5) Polycythemia due to an increase in erythropoietin
c.Chemical imbalance
(1) Hypocalcaemia stimulates parathyroid gland hyperplasia
(2) Iodine deficiency produces thyroid enlargement
Pathological
d.Viral infections
Example-epidermal hyperplasia (wart) due to human papillomavirus
e.Stimulating antibodies
Example-Graves' disease due to thyroid-stimulating antibodies (IgG) directed against thyroid-stimulating hormone receptors

9. Physiologic Hyperplasia
MECHANISM OF HYPERPLASIA
Most forms of pathologic hyperplasia are caused by excessive hormonal or growth factor stimulation
Physiologic Hyperplasia
Hormonal hyperplasia: E.g. Proliferation of the glandular epithelium of the female breast at puberty and during pregnancy Compensatory hyperplasia: E.g. when a liver is partially resected, mitotic activity in the remaining cells restores the liver to its normal weight. The stimuli are polypeptide growth factors
Proliferating fibroblasts and blood vessels aid in wound healing by growth factor stimulation
Pathologic Hyperplasia
Hormonal stimulation
If balance between estrogen and progesterone is disturbed, endometrial hyperplasia ensues Stimulation by Growth factors(GF)
Scars/keloid :Excessive proliferating of fibroblasts -GF produced by leucocytes
Viral infections E.g.papillomaviruses cause skin warts -GF produced by the virus or by infected cells.

10. Hypertrophy = Increase in the size of normal cell
Increase in cell size
Increase in the size of an organ or tissue
In hypertrophy there are no new cells, just bigger cells
Cells are enlarged by increased amounts of cytoplasm and cytoplasmic organelles in cells.
(1) In secretory cells, the synthetic apparatus—including the endoplasmic reticulum, ribosomes, and the Golgi zone—becomes prominent.
(2) In contractile cells such as muscle fibers, there is an increase in size of cytoplasmic myofibrils
Hypertrophy occurs when cells are incapable of dividing.
The striated muscle cells in both the skeletal muscle and the heart can undergo only hypertrophy in response to increased demand because in the adult they have limited capacity to divide

11. Causes of hypertrophy
Hypertrophy can be physiologic or pathologic caused either by increased functional demand or by specific hormonal stimulation.
The striated muscle cells in both the skeletal muscle and the heart can undergo only hypertrophy in response to increased demand because in the adult they have limited capacity to divide.
Physiological :
Therefore, the avid weightlifter can develop a rippled physique only by hypertrophy of individual skeletal muscle cells induced by an increased workload.
Muscle hypertrophy in athletes, both in the skeletal muscle of the limbs (as a response to increased muscle activity)
Pathological :
Left ventricular hypertrophy in response to an increase in afterload (resistance) or preload( hypertension or aortic valve disease )
Smooth muscle hypertrophy in the urinary bladder in response to urethral obstruction (e.g., prostate hyperplasia)
Surgical removal of one kidney with compensatory hypertrophy (and hyperplasia) of the other kidney
Cell enlargement in cytomegalovirus infections

12. Skeletal muscle hypertrophy

13. HYPERTENSION
Aortic valve stenosis LV
hypertrophy

14. ATROPHY Decrease in the size of a normally formed
tissue/organ resulting from a decreased
in the size of individual or
number of cells composing the tissue
Agenesis, aplasia / hypoplasia – abnormal organ
development

15. Definition ….. 15
AGENESIS – absence of an organ, resulting from failure of development (during embryogenesis)
APLASIA – complete failure of an organ / tissue development from its ..
HYPOPLASIA – incomplete development of an organ, size wise is smaller but structurally is normal

16. Atrophy = reduction in cell size and/or reduction in cell numbers
Shrinkage in the size of the cell by the loss of cell substance is known as atrophy.
Decrease in size of an organ or cell by reduction in cell size and/or cell numbers
When a sufficient number of cells is involved, the entire tissue or organ diminishes in size, weight becoming atrophic
Although atrophic cells may have diminished function, they are not dead.
Results from a reduction in the amount of cytoplasm and the number of cytoplasmic organelles; it is usually associated with diminished metabolism.
Tissues or cells affected by atrophy are said to be atrophic or atrophied.

17. Mechanism of atrophy Causes of atrophy
Decreased protein synthesis and increased protein degradation in cells. The degradation of cellular proteins occurs mainly by the ubiquitin-proteasome pathway
Increased autophagy, with resulting increases in the number of autophagic vacuoles. Autophagy ("self-eating") is the process in which the starved cell eats its own components in an attempt to find nutrients and survive. Residual organelle membranes often accumulate in the cytoplasm as brown lipofuscin pigment.
Loss of cells by apoptosis
Causes of atrophy
Physiological and Pathological causes
Physiological
Physiological atrophy occurs at times from very early embryological life, as part of the process of morphogenesis. The process of atrophy (mediated by apoptosis of cells) contributes to the physiological involution of organs such as the thymus gland in early adult life, and atrophy of many tissues in the body continues into late old age, where its results are regarded as the bane of existence

18. Causes of Atrophy - Pathological
Loss of blood supply - result of tissue hypoxia
Eg: Example-cerebral atrophy due to atherosclerosis of the carotid arteries.
Loss of endocrine stimulation Adrenal gland atrophies as a consequence of decreased ACTH secretion caused by destruction of the anterior pituitary (by a tumour or infarction), or as a result of the therapeutic use of high concentrations of corticosteroids
1818
'Pressure' atrophy due to tissues compression
(1)Exogenous agents (atrophy of skin in bedridden patients producing 'bed sores')
(2)Endogenous factors -tumour compression.
(3)Atrophy of the renal cortex and medulla in hydronephrosis
(3)Thick pancreatic duct secretions in cystic fibrosis occlude the lumens causing luminal back-pressure and compression atrophy of the exocrine glands and tubular epithelium
Hormone-induced atrophy
(1)Skin atrophy as a result of the growth-inhibiting actions of corticosteroids(applied topically in high concentrations cause dermal/epidermal atrophy)
(2) Adrenal atrophy – steroids absorbed in the skin can produce systemic side-effects
Brown atrophy is a tissue discoloration that results from lysosomal accumulation of lipofuscin ("wear and tear" pigment/an indigestible lipid derived from lipid peroxidation of cell membranes due to free radical damage of tissue.
Decreased innervation
■Eg.skeletal muscle atrophy due to loss of lower motor neurons in amyotrophic lateral sclerosis
Decreased function(Disuse atrophy)
E.g. limb immobilised due to fracture can cause muscle atrophy (physiotherapy required)
Senile Atrophy
Cell loss is common in aging process. Seen in permanent cells, brain & heart.
Lack of nutrition
(1)Muscle atrophy in marasmus (utilization of skeletal muscle as energy/protein (2) Cachexia in cancer.

19. Metaplasia = one type of mature cell is replaced by a different type of mature cell
Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell
Metaplasia is reversible.
Substituted cells are more resistant to a particular stress. (Cells sensitive to a particular stress are replaced by other cell types better able to withstand the adverse environment)
Metaplasia is thought to arise by genetic "reprogramming" of stem cells
Metaplasia is sometimes reversible if the irritant is removed.
Epithelial metaplasia is a double-edged sword; may predispose to malignant transformation of the epithelium. In fact, in a common form of lung cancer, squamous metaplasia of the respiratory epithelium often coexists with cancers composed of malignant squamous cells.

20. Causes of Metaplasia
Metaplasia from glandular to other types of glandular epithelium Example-pylorus and antrum epithelium shows an increase in goblet cells and Paneth cells in response to Helicobacter pylori-induced chronic atrophic gastritis- This is called intestinal metaplasia -Increased risk for developing dysplasia
Metaplasia from transitional to squamous epithelium
Schistosoma hematobium infection in the urinary bladder causes transitional epithelium to undergo squamous metaplasia.- risk for developing dysplasia
Replacement of columnar epithelium at the squamocolumnar junction of the cervix by squamous epithelium.
It can also occur in the endometrium & pancreatic ducts.
Squamous metaplasia of the bronchi with long-term use of tobacco &Vit A def. The "rugged" stratified squamous epithelium may be able to survive under circumstances that the more fragile specialized epithelium would not tolerate.
This process is often reversible.

21. Causes of Metaplasia Metaplasia from glandular to squamous epithelium
Epithelial metaplasia -Squamous metaplasia /Columnar metaplasia
Mesenchymal metaplasia-osseus metaplasia/Cartilaginous metaplasia
Metaplasia from glandular to squamous epithelium
(1) Main stem bronchus epithelium develops squamous metaplasia in response to irritants in cigarette smoke
(2) Endocervical epithelium develops squamous metaplasia in response to the acid pH in the vagina
Both of the above alterations have an increased risk for developing dysplasia .
Metaplasia from squamous to glandular epithelium
(1) In chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium
(2)Distal esophagus epithelium shows an increase in goblet cells and mucus-secreting cells in response to acid reflux This is called Barrett's esophagus. Increased risk for developing dysplasia

22. Metaplasia rarely occurs in mesenchymal tissue
Osseous metaplasia in scars and other fibroblastic proliferations. Osseous metaplasia is the formation of new bone at sites of tissue injury.
Cartilaginous metaplasia may also occur.
Myeloid metaplasia
Extramedullary hematopoiesis is proliferation of hematopoietictissue at sites other than the bone marrow, such as the liver or spleen

23. Mechanism of metaplasia
Metaplasia may result from reprogramming stem cells to utilize progeny cells with a different pattern of gene expression; the following signals may initiate this change:
(1) Hormones (e.g., estrogen)
(2) Vitamins (e.g., retinoic acid)
(3) Chemical irritants (e.g., cigarette smoke)

24. Endocervix, showing squamous metaplasia
Metaplasia of normal columnar (left) to squamous epithelium (right) in a bronchus, shown (A) schematically and (B) histologically

25. Dysplasia can be defined as the presence of neoplastic epithelium that is confined within the basement membrane of the gland within which it arises
Squamous epithelium of the uterine cervix, showing criteria used for grading dysplasia (cervical intraepithelial neoplasia). The maturation defect, the nuclear:cytoplasmic ratio, and the nuclear chromatin abnormalities progressively increase as the grade of dysplasia increases. Note that infiltration of the neoplastic cells through the basement membrane distinguishes invasive carcinoma from dysplasia and carcinoma in situ

26. Diagnosis of Dysplasia
Gross Examination
Many cases gross examination of the mucosa shows no abnormality.
Dysplasia can sometimes be identified through special examination techniques (eg, colposcopy for cervical dysplasia, fluorescent bronchoscopy for bronchial dysplasia) .
The Schiller test for cervical dysplasia :when the cervix is painted with iodine solution, normal squamous epithelium turns brown owing to its glycogen content; dysplastic epithelium remains unstained.
Microscopic Examination
The nuclear and cytoplasmic features of dysplastic tissue provides evidence for both diagnosis of dysplasia

27. Nuclear Abnormalities :Dysplasia is characterized by increased size of the nucleus, increased nuclear:cytoplasmic ratio; increased chromatin content (hyperchromatism); abnormal chromatin distribution (coarse clumping); and nuclear membrane irregularities such as thickening and wrinkling.
Cytoplasmic Abnormalities :result from failure of normal differentiation, eg, lack of keratinization in squamous cells and lack of mucin in glandular epithelium.
Increased Rate of Cell Multiplication : characterized by the presence of mitotic figures in many layers of the epithelium. Individual mitoses are morphologically normal in dysplasia.
Disordered Maturation
Significance of Dysplasia
Epithelial dysplasia is a premalignant lesion, associated with an increased risk of development of cancer.

28. Differences between Dysplasia & Neoplasia
Lack of Invasiveness :
Does not invade the basement membrane
Complete removal of the dysplastic area is therefore curative.
Cancer, in contrast, invades the basement membrane and spreads from the local (primary) site via lymphatics and blood vessels, so that excision of the primary site may not be curative.
Reversibility
Dysplastic tissue may sometimes spontaneously return to normal—unlike cancer, which is an irreversible process.
Severe dysplasia may be irreversible.