Unit 2 Part 2 Cell Adaptation, Injury & Death 2024-2025 PDF

UNIT 2 – INTRODUCTION TO PATHOLOGY Sarah Tan de Luna, MD, MPH PART 2 Cell Injury, Death, and Adaptation Sarah Tan de Luna, MD, MPH CELL ADAPTATION Pathology: the Study of Disease ◼ Etiology or cause: infection, genetic etc. and often mutifactoral ◼ Pathogenesis: progression of the diseas...

UNIT 2 – INTRODUCTION TO PATHOLOGY Sarah Tan de Luna, MD, MPH PART 2 Cell Injury, Death, and Adaptation Sarah Tan de Luna, MD, MPH CELL ADAPTATION Pathology: the Study of Disease ◼ Etiology or cause: infection, genetic etc. and often mutifactoral ◼ Pathogenesis: progression of the disease ◼ (Molecular and Morphologic Changes) ◼ Clinical Manifestations: signs and symptoms Injury: Altered Homeostasis  Overview ◼ Cells are the structural and functional units of tissues and organs. ◼ When a cell is exposed to physiologic or pathologic stress, it undergoes a reversible functional and structural response during which new but altered states are achieved allowing the cell to survive and to continue to function. ◼ This capability is called cellular adaptation. ◼ Adaptation results in a NEW STEADY STATE and PRESERVING VIABILITY Adapted-Normal-Injured Cells  Overview ◼ Whether a specific form of stress induces adaptation or causes reversible or irreversible injury depends not only on the nature and severity of the stress, but also on several other cell-specific variables, including vulnerability, differentiation, blood supply, nutrition, and the previous state of the cell Cell Proliferation Varies ◼ Labile cells – continuously dividing (epithelium, bone marrow, hematopoietic cells) ◼ Stable cells – quiescent (in G0 stage; hepatocytes, smooth muscle, lymphocytes, fibroblasts, endothelial cells) ◼ Permanent cells – nondividing (neurons, skeletal and cardiac muscle) Various Types of Adaptations ◼ Cells may undergo various adaptations in physiological and pathological conditions. These are controlled by complex molecular mechanisms.  Cellular Adaptations ◼ Hypertrophy ◼ Hyperplasia ◼ Atrophy ◼ Metaplasia ◼ Dysplasia*  Cellular Adaptations ◼ Physiologic – occurs due to a normal stressor/stimuli; results in enhanced function ◼ Pathologic – occurs due to an abnormal stressor/stimuli; results in dysfunction and mortality ◼ Compensatory – adaptation to positively counteract reduction in function Hypertrophy- ◼ Increase in the size of cells that results in an increase in the size of the affected organs. ◼ There are no new cells, just bigger cells, enlarged by an increased amount of structural proteins and organelles (increase in mRNA and proteins) Hypertrophy- ◼ Occurs in response to increased demands ◼ It is mostly seen in cells that cannot divide or multiply, such as:  skeletal muscle (pumping iron),  cardiac muscle (hypertension). ◼ These changes usually revert to normal if the cause is removed. Physiologic Hypertrophy Pathologic Hypertrophy ◼ Cross-section of the heart of a patient with long-standing hypertension shows pronounced, concentric left ventricular hypertrophy Hyperplasia- ◼ Increased number of cells in an organ or tissue in response to a stimuli. Hyperplasia may sometimes co-exist with hypertrophy. ◼ Takes place if the cell is capable of replication Mechanisms of Hyperplasia ◼ Growth factor-driven proliferation of mature cells and ◼ By increased output of new cells from tissue stem cells Physiologic Hyperplasia ◼ Female breast during pregnancy (epithelium) ◼ Liver - In individuals who donate one lobe of the liver for transplantation, the remaining cells proliferate so that the organ soon grows back to its original size ◼ Bone marrow in response to supplements ◼ Endometrium – after menstruation Physiologic Hyperplasia Pathologic Hyperplasia ◼ Endometrium – in response to hormones ◼ Hyperplasia of prostate in old age ◼ Epidermal hyperplasia (warts) in response to viral infection Pathologic Hyperplasia Hypertrophy and Hyperplasia Atrophy ◼ Shrinkage in the size of the cell by loss of substance ◼ When a sufficient number of cells is involved, the entire tissue or organ diminishes in size ◼ Although atrophic cells may have diminished function, they are not dead Atrophy results from both… ◼ Decreased protein synthesis ◼ Increased protein degradation -Lysosomes with hydrolytic enzymes -The ubiquitin-proteasome pathway Physiologic Atrophy ◼ Embryonic structures – notochord, thyroglossal duct ◼ Post partum uterus Physiologic Atrophy Pathologic Atrophy ◼ Disuse atrophy ◼ Denervation atrophy ◼ Ischemic atrophy ◼ Loss of nutrition – Marasmus, cachexia ◼ Loss of endocrine stimulation - Breast after menopause ◼ Pressure atrophy - Tumor compressing normal tissue Pathologic Atrophy Metaplasia ◼ A reversible change in which one ADULT cell type is replaced by another ADULT cell type that is able to withstand the adverse environment ◼ Reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. ◼ Usually occurs in response to stress or chronic irritation. Mechanisms of Metaplasia ◼ Re-programing of stem cells that exist in normal tissue. ◼ Induced by cytokines, growth factors and other environmental signals ◼ Retinoic acid may play a role. ◼ Exact mechanism is unknown. Squamous cells replace columnar cells Metaplasia ◼ Squamous metaplasia ◼ Osseous metaplasia ◼ Myeloid metaplasia Squamous Metaplasia Squamous Metaplasia Esophagus: glandular epithelium (R) is metaplastic Bronchus with Columnar to Squamous Metaplasia Esophagus with Squamous to Columnar metaplasia Endometrial Osseous Metaplasia Myeloid Metaplasia ◼ Atrophy, Hypertrophy, Hyperplasia and Metaplasia are reversible changes! ◼ Hyperplasia and Metaplasia are not premalignant changes, however they are “fertile fields” for Dysplasia which is a premalignant change Dysplasia ◼ Atypical proliferative changes due to chronic irritation or inflammation; ◼ Cells vary in size and shape, large nuclei are frequently present, and rate of mitosis is increased ◼ Premalignant change DYSPLASIA IN THE CERVIX Mild dysplasia Moderate Marked dysplasia dysplasia Anaplasia ◼ Cells are undifferentiated with variable nuclear and cell structures and numerous mitotic figures ◼ Characteristic of cancer and tumor and is the basis for grading the aggressiveness of a tumor Neoplasia ◼ “New growth” ◼ A tumor ◼ Benign – considered less serious because they do not spread and are not life threatening (except in the brain) ◼ Malignant - cancer Aplasia ◼ Failure of cell production. During fetal development, aplasia results in agenesis, or absence of an organ due to failure of production. Hypoplasia Incomplete development of an organ so that it fails to reach adult size; decrease in cell production that is less extreme than in aplasia. Examples of Hypoplasia Hypoplastic Left Ventricle Hypoplastic Kidney UNIT 2 – INTRODUCTION TO PATHOLOGY Sarah Tan de Luna, MD, MPH PART 2 Cell Injury, Death, and Adaptation Sarah Tan de Luna, MD, MPH CELL INJURY Cell Injury Overview of Cell Injury ◼ Cells actively control the composition of their immediate environment and intracellular milieu within a narrow range of physiological parameters (“homeostasis”) ◼ Under physiological stresses or pathological stimuli (“injury”), cells can undergo adaptation to achieve a new steady state that would be compatible with their viability in the new environment. Overview of Cell Injury ◼ When cells are exposed to inherently damaging agents, cells are stressed so severely that they are no longer able to adapt resulting in: ◼ Reversible cell injury – denotes pathologic changes that can be reversed when the stimulus is removed, or if the cause of injury is mild ◼ Irreversible injury – denotes pathologic changes that are permanent and cause cell death Timeline of Cell Injury Causes of Cellular Injury 1. Hypoxic Cell injury – oxygen deprivation a) Ischemia – loss of blood supply(oxygen and nutrients); more rapidly and severely injures tissues than does hypoxia alone b) Inadequate oxygenation – cardiorespiratory failure c) Loss of oxygen carrying capacity of blood – anemia, carbon monoxide poisoning Cell Proliferation Varies ◼ Labile cells – continuously dividing (epithelium, bone marrow, hematopoietic cells) ◼ Stable cells – quiescent (in G0 stage; hepatocytes, smooth muscle, lymphocytes, fibroblasts, endothelial cells) ◼ Permanent cells – nondividing (neurons, skeletal and cardiac muscle) Susceptibility of Cells to Hypoxic Injury High Neurons (3-4 min) Intermediate Myocardium, hepatocytes, renal epithelium (30 min-2hr) Low Fibroblasts, epidermis, skeletal muscle (many hours) Causes of Cellular Injury 2. Free Radical Injury ◼ ROS – Hydroxyl, Hydrogen, Superoxide ◼ Chemical species with a single unpaired electron in an outer orbital ◼ Chemically unstable and therefore react with other molecules, resulting in chemical damage ◼ Initiate autocatalytic reactions; molecules that react with free radicals are in turn converted to free radicals Free-Radical Induced Injury ◼ If not adequately neutralized, free radicals can damage cells by 1. Lipid peroxidation of membranes – double bonds in polyunsaturated membrane lipids are vulnerable to attack by oxygen free radicals Free-Radical Induced Injury 2. DNA fragmentation – Free radicals react with thymine in nuclear and mitochondrial DNA to produce single strands breaks 3. Protein cross-linking – Free radicals promote sulfhydryl-mediated protein cross linking, resulting in increased degradation and loss of activity Neutralization of Free Radicals 1. Spontaneous decay 2. Superoxide dismutase 3. Glutathione (GSH) 4. Catalase 5. Endogenous and exogenous antioxidants (Vitamins E, A, C and β carotene) Causes of Cellular Injury 3. Physical Agents – trauma, heat, cold, radiation, electric shock 4. Chemical Agents - a) Therapeutic drugs - paracetamol b) Nontherapeutic agents – lead, alcohol c) Binding of mercuric chloride to sulfhydryl groups of proteins d) Generation of toxic metabolites such as conversion of CCl4 to CCL3* free radicals in the SER of the liver Causes of Cellular Injury 5. Infectious Agents - a) Viruses b) Bacteria c) Fungi d) Rickettsia e) Parasites Infectious agents ◼ Infectious agents - direct effects of bacterial toxins; cytopathic effects of viruses and other actions such as:  interfering with DNA,RNA, proteins, cell membranes or  inducing apoptosis.  -indirect effects via the host immune reaction. Causes of Cellular Injury 6. Immune System - anaphylaxis, loss of immune tolerance leading to autoimmunity 7. Genetic Abnormalities - sickle cell disease, inborn errors of metabolism Causes of Cellular Injury 8. Nutritional imbalances – vitamin deficiencies, obesity leading to type II DM, fat leading to atherosclerosis 9. Aging – degeneration as a result of trauma, intrinsic cellular senesence Reversible Cell Injury ◼ Return to steady state by altering cell conditions ◼ Return to normal ◼ Sub-lethal and short lasting ◼ Caused by hypoxia/ischemia ◼ Best examples of reversible cell injury are cellular swelling and fat accumulation Reversible Cell Injury – Cell Swelling ◼ Cell swelling is the first manifestation of most forms of cell injury. ◼ Also called hydropic change or vacuolar degeneration ◼ Caused by failure of energy dependent ion pumps ◼ Gross changes: It causes some pallor, increased turgor, and increase in weight of the organ ◼ Microscopic changes: Small, clear vacuoles seen in the cytoplasm which represent distended and pinched off segments of ER Reversible Cell Injury – Cell Swelling Reversible Cell Injury – Fatty Change ◼ Steatosis/Fatty change occurs in hypoxic, toxic or metabolic injuries. ◼ It is characterized by the appearance of lipid vacuoles in the cytoplasm. ◼ Abnormal accumulations of triglycerides within parenchymal cells ◼ These changes are encountered by the cells involved in the fat metabolism such as hepatocyte, myocardial cells, muscle, kidney. Reversible Cell Injury – Fatty Change PREVALENCE OF FATTY LIVER DISEASE ◼ Global Prevalence of NAFLD estimated at 38% in 2018. ◼ Prevalence in the Philippines: -12.2% at a tertiary hospital in 2008 -38-39% in two small series in private hospitals in 2015 and 2020 Other Ultrastructural Changes Plasma membrane blebbing Plasma membrane blunting Distortion of microvilli Creation of myelin figures Loosening of intercellular attachments Plasma Membrane Blebbing ◼ Membrane blebs are formed when plasma membrane is detached from underlying actin cytoskeleton. ◼ The detachment is caused by the increase of intracellular pressure or by the local rupture of actin filaments. Myelin Figures ◼ Aggregates of damaged cell membranes (phospholipids). ◼ They either are phagocytosed by other cells or further degraded into fatty acids and calcify. Myelin Figures Other Ultrastructural Changes Mitochondrial swelling Mitochondrial rarefaction Small phospholipid- rich amorphous densities Other Ultrastructural Changes Endoplasmic reticulum - Dilation of the ER leads to the detachment and disaggregation of polysomes Nucleus - Disaggregation of granular and fibrillar elements Irreversible Cell Injury ◼ Severe types of cell injury, leads to cell death ◼ Has passed the point of no return ◼ Lethal and long lasting ◼ Results in NECROSIS an APOPTOSIS ◼ Leads to permanent cell loss Mechanisms of Cell Injury (Necrosis/Apoptosis) CELL DEATH Cell Death ◼ Death of cells occurs in two ways:  Necrosis--(irreversible injury) changes produced by enzymatic digestion of dead cellular elements  Apoptosis--vital process that helps eliminate unwanted cells--an internally programmed series of events effected by dedicated gene products Necrosis ◼ Morphologic expression of cell death ◼ Progressive disintegration of cell structure ◼ Initiated by overwhelming stress ◼ Usually elicits an acute inflammatory cell response (neutrophils may be present). Necrosis ◼ Result from denaturation of intracellular proteins and enzymatic digestion of cells ◼ Loss of membrane integrity ◼ Digestion enzyme: from lysosomes of dying cells and from leukocytes (inflammatory response) ◼ Vacuolation due to digestion of cytoplasmic organelles ◼ Plasma and membrane discontinuities Types of Necrosis Patterns of Necrosis In Tissues or Organs – Macroscopic Changes Coagulative necrosis: ◼ Typically seen in hypoxic environments (ischemia caused by obstruction in a vessel) ◼ The outline of the dead cells are maintained and the tissue is somewhat firm. ◼ The injury denatures not only structural proteins but also enzymes and so blocks the proteolysis of the dead cells ◼ Example: myocardial infarction Coagulative Necrosis Coagulative Necrosis Coagulative Necrosis ◼ When there is marked cellular injury, there is cell death. This microscopic appearance of myocardium is a mess because so many cells have died that the tissue is not recognizable. Many nuclei have become pyknotic (shrunken and dark) and have then undergone karorrhexis (fragmentation) and karyolysis (dissolution). The cytoplasm and cell borders are not recognizable. Morphology of necrosis – cytoplasmic changes Increased ◼ Gross eosinophilia due to Loss of ◼ Microscopy Inflammatio cytoplasmic RNA n that binds Cellular ◼ Ultrastructure (Electron microscopy) hematoxylinswelling When enzymes have digested the cytoplasmic organelles, the cytoplasm becomes vacuolated and appears moth- eaten Source: Robbins Textbook of pathology, 9E Patterns of Necrosis In Tissues or Organs – Macroscopic Changes  Liquefactive necrosis: the dead cells undergo disintegration and affected tissue is liquified. ◼ Example: cerebral infarction. ◼ usually associated with cellular destruction and pus formation (e.g. pneumonia). ◼ ischemia (restriction of blood supply) in the brain produces liquefactive rather than coagulative necrosis. Brain Abscess with Liquefactive Necrosis Abscess/Liquefactive Necrosis Liquefactive necrosis ◼ This is liquefactive necrosis in the brain in a patient who suffered a "stroke" with focal loss of blood supply to a portion of cerebrum. This type of infarction is marked by loss of neurons and neuroglial cells and the formation of a clear space at the centre left. Patterns of Necrosis In Tissues or Organs – Macroscopic Changes ◼ Caseous necrosis:  specific form of coagulation necrosis typically caused by mycobacteria (e.g. tuberculosis).  a form of coagulative necrosis.  The term “caseous” (cheese like) is derived from the friable white appearance of the area of necrosis  Example: tuberculosis lesions. ◼ Caseous necrosis hilar lymph node lung Granulomatous Inflammation with Central Necrosis Patterns of Necrosis In Tissues or Organs – Macroscopic Changes ◼ Gangrenous necrosis:  Necrosis (secondary to ischemia)  usually with superimposed infection.  Example: necrosis of distal limbs, usually foot and toes in diabetes. Gangrenous Necrosis Gangrenous Necrosis ◼ In this case, the toes were involved in a frostbite injury. This is an example of "dry" gangrene in which there is mainly coagulative necrosis from the anoxic injury. Patterns of Necrosis In Tissues or Organs – Macroscopic Changes ◼ Fibrinoid necrosis is caused by immune- mediated vascular damage. This pattern of necrosis typically occurs when complexes of antigens and antibodies are deposited in the walls of arteries. ◼ Deposits of these “immune complexes,” together with fibrin that has leaked out of vessels, result in a bright pink and amorphous appearance in H&E stains, called “fibrinoid” (fibrin-like) by pathologists. Patterns of Necrosis In Tissues or Organs – Macroscopic Changes Patterns of Necrosis In Tissues or Organs – Macroscopic Changes ◼ Fatnecrosis: Traumatic fat necrosis Enzymatic fat necrosis - necrosis of fat by pancreatic enzymes. Fat Necrosis ◼ This is fat necrosis of the pancreas. Cellular injury to the pancreatic acini leads to release of powerful enzymes which damage fat by the production of soaps, and these appear grossly as the soft, chalky white areas seen here on the cut surfaces. Fat Necrosis Fat Necrosis (L) and Normal Pancreas (R) Patterns of Necrosis In Tissues or Organs – Macroscopic Changes  Gummatous necrosis is restricted to necrosis involving spirochaetal infections (e.g. syphilis). Patterns of Necrosis In Tissues or Organs – Macroscopic Changes  Haemorrhagic necrosis is due to blockage of the venous drainage of an organ or tissue (e.g. in testicular torsion). Apoptosis ◼ Pathway of cell death induced by a tightly regulated suicide program. ◼ Controlled by specific genes. ◼ Fragmentation of nucleus, DNA ◼ Blebs form and apoptotic bodies are released. ◼ Apoptotic bodies are phagocytized. ◼ No neutrophils. Apoptosis ◼ In the human body ~ 100,000 cells are produced every second by mitosis and a similar number die by apoptosis. ◼ Development and morphogenesis  During limb formation separate digits evolve  Ablation of cells no longer needed (tadpole) ◼ Homeostasis  Immune system  >95% T and B cells die during maturation (negative selection) ◼ Deletion of damaged/ dangerous cells Causes of Apoptosis ◼ Physiologic ◼ Pathologic Physiologic Apoptosis ◼ Hormone dependent involution - Prostate glandular epithelium after castration; Regression of lactating breast after weaning, endometrium in menstrual cycle, mammary gland in menopause ◼ Cell loss in proliferating cell populations – Immature lymphocytes, Epithelial cells in the GI tract Physiologic Apoptosis ◼ Elimination of self-reactive lymphocytes ◼ Death of cells that have served their function – neutrophils in acute inflammation ◼ During development for removal of excess cells during embryogenesis - Programmed cell destruction, for example formation of digits Apoptosis (Cell Death) Apoptosis (Cell Death) Apoptosis (Cell Death) Pathologic Apoptosis ◼ To eliminate cells with DNA damage by radiation, cytotoxic agents etc. ◼ Accumulation of misfolded proteins - Improperly folded proteins may arise because of mutations. Excessive accumulation of these proteins in the ER leads to a condition called ER stress ◼ Cell death in viral infections that induce apoptosis such as HIV and Adenovirus ◼ Alzheimer's, Parkinson's and Huntington's diseases, and stroke Pathologic Apoptosis ◼ Councilman bodies in liver - Apoptotic Body or Councilman Hyaline Body; eosinophilic globule that represents a hepatocyte undergoing apoptosis and sometimes necrosis; seen most commonly in Yellow fever and other viral hemorrhagic fevers ◼ Organ atrophy after duct obstruction - in the pancreas, parotid gland, and kidney Initiation of Apoptosis ◼ Intrinsic Pathway - Begins when an injury occurs within the cell and the resulting stress activates the apoptotic pathway; activated when BCL-2-family pro-apoptotic proteins cause the permeabilization of the mitochondrial outer membrane Initiation of Apoptosis ◼ Extrinsic Pathway - Begins outside a cell, when conditions in the extracellular environment determine that a cell must die; activated when cell-surface death receptors like Fas are engaged by their ligands Mechanisms of apoptosis Morphology of Apoptosis ◼ Cell shrinkage ◼ Chromatin condensation ◼ Formation of cytoplasmic blebs and apoptotic bodies ◼ Phagocytosis of apoptotic cells or cell bodies, usually by macrophages Necrosis vs Apoptosis INTRACELLULAR ACCUMULATIONS INTRACELLULAR ACCUMULATIONS ◼ Metabolic derangements lead to accumulation of different substances in the cytoplasm or in organelles or in nucleus PATHWAYS Source: Robbins Textbook of pathology, 9E LIPID ◼ Fatty change ◼ Atherosclerosis ◼ Xanthomas ◼ Cholesterosis Fatty Change ◼ Characterized by the accumulation of intracellular parenchymal triglycerides and is observed most frequently in the liver, heart, and kidney. ◼ For example, in the liver, fatty change may be secondary to alcoholism, diabetes mellitus, malnutrition, obesity, or poisonings. ◼ Cause: Imbalance among the uptake, utilization, and secretion of fat Fatty Change Mechanisms ◼ Increased transport of triglycerides or fatty acids to affected cells ◼ Decreased mobilization of fat from cells, most often mediated by decreased production of apoproteins required for fat transport. ◼ Decreased use of fat by cells ◼ Overproduction of fat in cells Atherosclerosis ◼ In atherosclerotic plaques, smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles, most of which are made up of cholesterol and cholesterol esters. ◼ Such cells have a foamy appearance (foam cells) Xanthomas ◼ Clusters of foamy cells are found in the subepithelial connective tissue of the skin and in tendons Cholesterosis ◼ This refers to the focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder PROTEINS ◼ Resorption droplets in proximal renal tubules in proteinuria ◼ Russel bodies ◼ α1 antitrypsin deficiency ◼ Neurofibrillary tangle found in Alzheimer’s HYALINE CHANGE ◼ An alteration within cells or in the extracellular space that gives a homogeneous, glassy, pink appearance in routine histologic sections stained with hematoxylin and eosin ◼ This morphologic change is produced by a variety of alterations and does not represent a specific pattern of accumulation HYALINE CHANGE ◼ Intracellular Hyaline  Intracellular accumulations of protein, described earlier (reabsorption droplets, Russell bodies, alcoholic hyaline), are examples of intracellular hyaline deposits. HYALINE CHANGE ◼ Extracellular Hyaline  Collagenous fibrous tissue in old scars may appear hyalinized  In long-standing hypertension and diabetes mellitus, the walls of arterioles, especially in the kidney, become hyalinized, resulting from extravasated plasma protein and deposition of basement membrane material GLYCOGEN ◼ Glycogen is a readily available energy source stored in the cytoplasm of healthy cells. ◼ Excessive intracellular deposits of glycogen are seen in patients with an abnormality in either glucose or glycogen metabolism – Diabetes mellitus/Glycogen storage disorders PIGMENTS ◼ Carbon ◼ Lipofuscin ◼ Hemosiderin ◼ Melanin ◼ Homogentisic acid ◼ Bilirubin Carbon ◼ The most common exogenous pigment is carbon (coal dust), a ubiquitous air pollutant in urban areas. ◼ ANTHRACOSIS  When inhaled Carbon is picked up by macrophages within the alveoli and is then transported through lymphatic channels to the regional lymph nodes  Accumulations of this pigment blacken the tissues of the lungs and the involved lymph nodes. ◼ COAL WORKER’S PNEUMOCONIOSIS  In coal miners the aggregates of carbon dust may induce a fibroblastic reaction or even emphysema and thus cause a serious lung disease. ◼ TATTOOING  is a form of localized, exogenous pigmentation of the skin. The pigments inoculated are phagocytosed by dermal macrophages, in which they reside for Source: Robbins Textbook of pathology, 9E the remainder of the  The pigments do not usually evoke any Inflammatory response. Lipofuscin ◼ It is seen in cells undergoing slow, regressive changes and is particularly prominent in the liver and heart of aging patients ◼ Tell-tale sign of free radical injury and lipid peroxidation ◼ Not injurious to the cell or its functions Hemosiderin ◼ Hemosiderin, a hemoglobin-derived, golden yellow to-brown, granular or crystalline pigment derived from iron ◼ Under normal conditions small amounts of hemosiderin can be seen in the mononuclear phagocytes of the bone marrow, spleen, and liver, which are actively engaged in red cell breakdown ◼ Local excesses of hemosiderin - Common bruise Hemosiderin Hemosiderin ◼ Systemic overload of iron - HEMOSIDEROSIS  Hemochromatosis - increased absorption of dietary iron due to an inborn error of metabolism called  Hemolytic anemias - premature lysis of red cells leads to release of abnormal quantities of iron  Repeated blood transfusions - transfused red cells constitute an exogenous load of iron Melanin ◼ Formed from tyrosine by the action of tyrosinase, synthesized in melanosomes of melanocytes within the epidemis, and transferred by melanocytes to adjacent clusters of keratinocytes and also to macrophages (melanophores) in the subjacent dermis. ◼ Increased melanin pigmentation is associated with sun tanning and with a wide variety of disease conditions. ◼ Decreased melanin pigmentation is observed in albinism and vitiligo. Homogentisic acid ◼ Black pigment that occurs in patients with alkaptonuria ◼ Here the pigment is deposited in the skin, connective tissue, and cartilage, and the pigmentation is known as Source: Robbins Textbook of pathology, 9E oochronosis Bilirubin ◼ This pigment is a catabolic product of the heme moiety of hemoglobin and, to a minor extent, myoglobin. ◼ In various pathologic conditions, bilirubin accumulates and stains the blood, sclera, mucosae, and internal organs, producing a yellowish discoloration called jaundice. PATHOLOGIC CALCIFICATION ◼ Pathologic calcification is the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts ◼ Types  Dystrophic  Metastatic Dystrophic Calcification ◼ Deposition occurs locally in dying tissues ◼ It occurs despite normal serum levels of calcium ◼ In absence of derangements in calcium metabolism Dystrophic Calcification ◼ Examples  in the atheromas of advanced atherosclerosis  develops in aging or damaged heart valves ◼ Morphology  Gross - fine, white granules or clumps, often felt as gritty deposits  Microscopy – ◼ intracellular or extracellular, basophilic, amorphous granular, sometimes clumped appearance ◼ The progressive acquisition of outer layers may create lamellated configurations, called psammoma bodies – In papillary lesions of thyroid, Source: Robbins Textbook of pathology, 9E meningiomas etc ◼ In asbestosis of the lung, iron and calcium deposition creates dumbbell shaped forms Metastatic Calcification ◼ Deposition of calcium salts in otherwise normal tissues ◼ Results from hypercalcemia ◼ Secondary to some disturbance in calcium metabolism. Metastatic Calcification ◼ Principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins ◼ All of these tissues excrete acid and therefore have an internal alkaline compartment that predisposes them to metastatic calcification Metastatic Calcification - Causes  Increased secretion of parathyroid hormone (PTH) with subsequent bone resorption ◼ hyperparathyroidism due to parathyroid tumors, and ◼ ectopic secretion of PTH-related protein by malignant tumors  Resorption of bone tissue ◼ primary tumors of bone marrow (e.g., multiple myeloma, leukemia) ◼ diffuse skeletal metastasis (e.g., breast cancer), accelerated bone turnover (e.g., Paget disease) ◼ Immobilization Metastatic Calcification - Causes  Vitamin D–related disorders ◼ vitamin D intoxication, ◼ sarcoidosis (in which macrophages activate a vitamin D precursor ◼ idiopathic hypercalcemia of infancy (Williams syndrome) - characterized by abnormal sensitivity to vitamin D  Renal failure ◼ which causes retention of phosphate, leading to secondary hyperparathyroidism.