CELL INJURY for Medical (lecture 3) Sufia Husain Assistant Prof & Consultant KKUH, Riyadh.

Objectives 1. PATHOLOGIC CALCIFICATION 2. ADAPTATION TO INJURY

Pathologic Calcification Pathologic calcification is the abnormal tissue deposition of calcium salts. There are two forms of pathologic calcification. 1. The deposition of calcium in locally in dying or injured tissue is known as dystrophic calcification. In dystrophic calcification the serum levels of calcium are normal and the calcium metabolism is normal. 2. The deposition of calcium salts in otherwise normal tissues is known as metastatic calcification. In metastic calcification there is hypercalcemia secondary and abnormal calcium metabolism.

Dystrophic calcification Seen in areas of necrosis and/or damage e.g. in the atheromas of advanced atherosclerosis in aging or damaged heart valves. Tuberculous lesions, sometimes a tuberculous lymph node is virtually converted to stone In fat necrosis. Psammoma body (see later) Areas of trauma

Metastatic calcification Caused by hypercalcemia and occur in normal tissue. There are four principal causes of hypercalcemia: 1. Most commonly due to hyperparathyroidism (increased secretion of parathyroid hormone /PTH) with subsequent bone resorption. 2. Destruction of bone tissue by osteolytic bone tumors e.g. multiple myeloma, leukemia or metastatic bone cancers. This leads to mobolization of Ca2+ and phosphates. 3. Hypervitaminosis D 4. Renal failure, which causes retention of phosphate, leading to secondary hyperparathyroidism 5. Excess calcium intake e.g. milk-alkali syndrome.

Pathologic Calcification

Morphology of pathologic calcification (dystrophic or metastatic, both look the same) Ca deposition occurs anywhere in the body e.g. in wall of blood vessels, kidneys, lungs, stomach, skin etc. Whatever the site of deposition, the calcium salts appear macroscopically as fine, white granules or clumps, often felt as gritty deposits. Histologically, calcium salts are basophilic, amorphous granular. They can be intracellular, extracellular, or both. In the course of time, heterotopic bone may be formed in the focus of calcification. Psammoma body is a type of dystrophic calcification made up of a round collections of calcium, seen microscopically. They are concentric lamellated calcified structures, They are seen in papillary cancers in the body (e.g. thyroid, ovary, kidney) and in meningiomas of the brain.

Pathologic Calcification

Psammoma bodies

Adaptation to environmental stress

Cells are constantly adjusting their structure and function to accommodate changing demands and extracellular stresses i.e. they adapt within physiological limits. As cells encounter physiologic stresses or pathologic stimuli, they can undergo adaptation.The principal adaptive responses are hypertrophy, hyperplasia, atrophy, and metaplasia. Increased demands lead to hypertrophy and hyperplasia. Reduced demand leads to atrophy. Tissue cells can also adapt by changing or differentiating to another type of cell. This is known as metaplasia. If the adaptive capability is exceeded or if the external stress is harmful, cell injury develops. Within certain limits injury is reversible, and cells return to normal but severe or persistent stress results in irreversible injury and death of the affected cells.

Hypertrophy Is an increase in the size of the organ or tissue due to the increase in the size of the cells. In addition there is an increase in protein synthesis and an increase in size and number of intracellular organelles. Hypertrophy takes place in cells that are not capable of dividing e.g. striated muscles. Hypertrophy can be physiologic or pathologic and is caused either by increased functional demand or by specific hormonal stimulation. Physiological example: the striated skeletal muscles undergo only hypertrophy in response to increased demand by exercise. Examples of pathologic cellular hypertrophy include the cardiac enlargement that occurs with hypertension or aortic valve disease.

Hyperplasia Is the increase in the size of an organ or tissue caused by an increase in the number of cells. Hyperplasia takes place if the cell population is capable of replication. Hyperplasia can be physiologic or pathologic. A) Physiologic hyperplasia are of two types 1.Hormonal hyperplasia e.g. the proliferation of the glandular epithelium of the female breast at puberty and during pregnancy 2.Compensatory hyperplasia is hyperplasia that occurs when a portion of the tissue is removed or diseased. For example, when a liver is partially resected, the remaining cells multiply eventually restoring the liver to its normal weight. B) Pathologic hyperplasia are caused by abnormal excessive hormonal or growth factor stimulation e.g. if the balance between estrogen and progesterone is disturbed, endometrial hyperplasia ensues, leading to abnormal menstrual bleeding. Sometimes pathologic hyperplasia acts as a fertile soil in which cancerous proliferation may eventually arise. Thus, patients with hyperplasia of the endometrium are at increased risk of developing endometrial cancer.

Hypertrophy and hyperplasia Hypertrophy and hyperplasia can occur together, e.g. there is massive physiologic enlargement of the uterus during pregnancy in which there is smooth muscle hypertrophy and smooth muscle hyperplasia.

Atrophy Shrinkage in the size of the cell by the loss of cell substance is known as atrophy. When a sufficient number of cells are involved, the entire tissue or organ diminishes in size, becoming atrophic. Atrophic cells may have diminished function, they are not dead. Causes of atrophy include decreased workload or disuse(e.g. immobilization of a limb in fracture), loss of innervation (lack of neural stimulation to the peripheral muscles caused by injury to the supplying nerve results in wasting/atrophy of that muscle) diminished blood supply, inadequate nutrition loss of endocrine stimulation aging (senile atrophy). Some of these stimuli are physiologic (e.g. the loss of hormone stimulation in menopause) and others pathologic (e.g., denervation) Atrophy represents a retreat by the cell to a smaller size at which survival is still possible; a new equilibrium is achieved between cell size and diminished blood supply, nutrition, or trophic stimulation. In atrophy there is decreased protein synthesis and increased protein degradation in cells.

Involution It is the reduction in the cell number.

Hypoplasia and aplasia Hypoplasia refers to an organ that does not reach its full size. It is related to developmental disorders rather than being an adaptive response e.g. partial lack of growth and maturation of gonadal structures in Turner or Klienfelter syndrome. Aplasia is the failure of cell production and it is also usually related to developmental disorders rather than being an adaptive response e.g. during fetal growth aplasia can lead to agenesis of organs and aplasia in bone marrow (pathological) can cause aplastic anemia.

Metaplasia Is the replacement of one mature type of cells by another mature type of cells. Metaplasia is usually a reversible change provided the causative stress factor is removed. It is a type of cellular adaptation in which, cells sensitive to a particular stress are replaced by other cell types better able to withstand the adverse environment. Examples include: 1.Squamous metaplasia: 2.Columnar cell metaplasia 3.Osseous metaplasia 4.Myeloid metaplasia

1) Squamous metaplasia  In cervix: replacement of columnar epithelium at the squamocolumnar junction of the cervix by squamous epithelium.  In respiratory tract: the columnar epithelium of the bronchus is replaced by squamous cell following chronic injury in chronic smokers. The squamous epithelium is able to survive under circumstances that the more fragile specialized epithelium would not tolerate. Although the metaplastic squamous epithelium has survival advantages, important protective mechanisms of columnar epithelium are lost, such as mucus secretion and ciliary clearance of particulate matter. If the influences that induce metaplastic transformation persists, it may predispose to malignant transformation of the epithelium. In fact, it is thought that cigarette smoking initially causes squamous metaplasia, and squamous cell cancers arise from it. Squamous cell carcinoma of cervix also arises from the metaplastic squamous epithelium

Columnar, osseous and myeloid metaplasia 2) Columnar cell metaplasia: It is the replacement of the squamous lining of the esophagus by columnar cells. It is seen in chronic gastric reflux in which the normal stratified squamous epithelium of the lower esophagus undergoes metaplastic transformation to columnar epithelium. This change is called as Barrett’s oesophagus and it can be precancerous and lead to development of adenocarcinoma of esophagus. 3) Osseous metaplasia: it is the formation of new bone at sites of tissue injury. Cartilagenous metaplasia may also occur. 4) Myeloid metaplasia (extramedullary hematopoiesis): is the proliferation of hematopoietic tissue in sites other then the bone marrow such as liver or spleen.