Pathology Notes PDF

Pathology Robins for basic pathology Dr. Dala Daraghmeh Ph.D pharmacology, Pharm.d Email: [email protected]  Topics to be covered Cell injury, adaptation, and death Inflammation – Acute inflammation – Chroni...

Pathology Robins for basic pathology Dr. Dala Daraghmeh Ph.D pharmacology, Pharm.d Email: [email protected]  Topics to be covered Cell injury, adaptation, and death Inflammation – Acute inflammation – Chronic inflammation Tissue repair, regeneration and fibrosis Hemodynamic disorders Neoplasia Blood vessels and heart disorders 2  Learning Outcomes Define pathology and discuss the core aspects of disease in pathology Know pathology divisions Explain what is meant by cellular adaptation and homeostasis Know the causes of cell injury Define hyper/hypo/atrophy and hyperplasia and give example on each Recognize the difference between hyperplasia and hypertrophy 3  Introduction Definition of pathology: Literally translated: Study of suffering The field of pathology is devoted to understand the cause of the disease and the changes in cells, tissue and organs that are associated with the disease and give rise to the presenting signs and symptoms in patients.  Divisions of Pathology General Systemic Pathology Pathology  General Pathology The basic ways in which cells & tissues respond to stimuli: 1. Cell injury / Adaptation 2. Inflammation 3. Repair  Systemic pathology The particular responses of the specialized organs: Infarction in heart Infarction in brain Infarction in intestine  What do we study in pathology? 1. Terminology of diseases 2. Etiological factor(s): Some diseases have a single etiology others have multiple etiological factors. 3. Pathogenesis: Mechanisms through which etiology results in structural & functional changes in the cells, tissues, organs leading to manifestations of the disease. 4. Morphology: Pathological gross and microscopic changes in the cells and tissues induced by the disease. What do we study in pathology? 5. Clinical symptoms & signs: Features that bring the patient to seek medical advice. 6. Natural history: Disease’s origin => Progression & Outcome (prognosis). No investigations or treatment is included in the pathology. Cell injury, adaptation and death  Cell injury 1. Homeostasis: The cells survive, function & interact within their immediate environment & the intracellular milieu within a relatively narrow range of physiological parameters. 2. Adaptation: Under a certain degree of stimuli (physiological or pathological stress). “The cells try to achieve a new steady state & preserve viability.”  Cont. if the adaptive capability of the cells is exceeded, or the injury was severe enough from the start to overcome the adaptation capacity, then cell injury will occur.  Cell injury 3. Reversible: If the stimulus is removed, and under certain limits, the injury can be reversed and the cells can return back to their stable status 4. Irreversible: If the limits are exceeded, the cells will lose viability & die (Cell death) o Necrosis: Death of cells within viable organs (Pathological) o Apoptosis: Programmed cell death. (Pathological & Physiological)  Cell injury, adaptation and death The cell and the Environment Homeostasis New level Injury Cell death Adaptation  Causes of cell injury 1. Hypoxia (Oxygen deprivation): Oxygen deficiency; interferes with the aerobic oxidative respiration. One of the most common causes of cell injury  Causes of cell injury Ischemia: Loss of blood supply in a tissue due to impairment of the blood supply or the venous drainage. - The most common cause of hypoxia. - The most common cause of cell injury. - More injurious than hypoxia, because it impairs the delivery of oxygen & glycolysis substrate as well as the removal of waste.  Causes of hypoxia Ischemia Inadequate oxygenation of blood: Pneumonia Carbon monoxide poisoning Anemia  Causes of cell injury 2. Chemicals: Whether known chemical injurious agents, or even normal substrates in abnormal concentrations. 3. Infectious agents: Bacteria & Viruses 4. Immunological reactions: Antigen – antibody reactions are meant to protect the host, but if overridden will result in: A. Hypersensitivity reaction pattern B. Autoimmune disorders  Causes of cell injury 5. Genetic defects (e.g. dawn syndrome) 6. Nutritional imbalance: Over or under nutrition. This includes vitamins & minerals. 7. Physical agents: Thermal, electrical, radiation, trauma. 8. Aging - Cellular senescence: Intrinsic aging of the cells, leading to alternations in the replicative and the repair abilities.  Cellular adaptation Definition: A new steady state which lies between normal unstressed cell, and the injured overstressed cell, in which the cell can function and preserve viability.  Cellular adaptation Stresses can be: 1. Physiological: Leading to physiological adaptation, (hormones leading to enlargement of the breast and the uterus during pregnancy). 2. Pathological: Leading to pathological adaptation, (hormones produced by tumors leading to endometrial hyperplasia).  Cellular adaptation The adaptive stimulus can act at any step: - Cell membrane/receptor binding - Signal transduction - Protein transcription, translation or export All adaptive responses are reversible, if the underlying cause is abolished.  Cellular adaptation Types of adaptive responses: Atrophy (Reduction in size and cell number) Hypertrophy (Enlargement of individual cells) Hyperplasia (Increase in cell number) Metaplasia (Transformation from one type of epithelium to another)  Cellular adaptation- Atrophy Decrease in the size of the cell, due to the loss of the cell substances, leading to diminished function of the cell and a new equilibrium is reached. - This is accompanied by decrease in the size of the organ, if sufficient number of cells is involved. - The cells are alive “Not dead” - Imbalance between protein synthesis and degradation is the fundamental step, leading to reduction in structural components.  Causes of atrophy Physiological: - Thymic involution, Aging - Age 0-15 years (large size) - Age 15-25 years (decrease in the size) Pathological: Decrease work load (Disuse) Loss of innervation (Denervation) Diminished blood supply (Ischemic) Inadequate nutrition Loss of hormonal stimuli  Mechanisms of atrophy: Identical in physiological and pathological causes. Imbalance between the protein synthesis and degradation, with degradation playing a major role.  Autophagy and cell atrophy lysosomes: act on exogenous proteins engulfed by endocytosis or subcellular components leading to the formation of autophagic vacuoles, which are increased in atrophy.  Mechanisms of atrophy: ubiquitin-proteasome pathway: – acts on cytosolic and nuclear proteins. – The protein/ubiquitin complex are engulfed by the cytoplasmic proteasome  Mechanisms of atrophy Sometimes the number of cells can be reduced by the process apoptosis of, which is under the same influences as the atrophy. Histologic Changes Decreased cell size Increased autophagic vacuoles Increased residual bodies (lipofuscin)  Hypertrophy Increase in the size of cells by an increase in the number and density of the cellular substances, leading to an over all increase in the size and the function of the organ, and a new equilibrium is reached.  Hypertrophy Mainly occurs in organs composed of cells that can’t divide (cardiac muscles). This is not accompanied by an increase in the number of the cells. Causes: Physiological or pathological: – Increase in the work load (body building, hypertension). – Increase in hormonal stimulation. This involves both hypertrophy and hyperplasia.  Hypertrophy Mechanisms: Increase in the synthesis of structural proteins/cell, leading to an overall increase in the workload of the organ. Cardiac muscle hypertrophy in hypertension Skeletal muscle hypertrophy in body building:  Hyperplasia An increase in the size of the organ due to increase in the number of the cells in the organ, leading to increase in the function. This is seen in cells that can divide. Hyperplasia: In many instances, hyperplasia and hypertrophy occur at the same time. Uterus during pregnancy is a good example.  Hyperplasia Causes Physiological: – Hormonal hyperplasia. – Compensatory hyperplasia: which is under the influence of growth factors, liver resection. Pathological: – Under the effect of hormones or growth factors. Endometrial hyperplasia is an example.  Hyperplasia Both hypertrophy and hyperplasia are reversible, if the stimulus is removed. Persistence of the stimulus any change the process into neoplasia “cancer” Hypertrophy & Hyperplasia  Metaplasia Replacement of one type of adult cell, whether epithelial or mesenchymal, by another type of adult cell, aiming at replacing cells that are sensitive to certain stimuli by a more resistant cell type. This happens through reprogramming of stem cells or undifferentiated mesenchymal cells. Examples of Metaplasia  Subcellular responses to injury: lysosomal catabolism: – Primary lysosomes: membrane bound intracellular organelles containing a variety of hydrolytic enzymes – Secondary lysosomes, “phagolysosome” : when the 1ry lysosomes fuse with vacuoles containing material for digestion.  Type of phagocytosis: Autophagy: – When intracellular organelles are sequestered from the cytoplasm in an autophagic vacuole. This combines with 1ry lysosome to form autophagolysosome. – This is seen especially with atrophy, aging, development and remodeling.  Type of phagocytosis: Heterophagy: – Inflammatory cells engulf and destroy foreign bodies e.g. microorganisms or foreign material by the process of endocytosis: Pinocytosis: is engulfment of soluble material. Phagocytosis: engulfment of large material. – Endocytic vacuoles combine with 1ry lysosomes to form heterophagic phagolysosomes If carbohydrate, completely digested. If lipid, residual bodies, lipofuscin pigment. Some foreign material can stay within cells like carbon particles. lipofuscin  Mitochondrial alternations: increase number in hypertrophy, decrease in atrophy increase in the size in alcoholic liver (megamitochondria)  Heat shock proteins; HSP Synonymous: stress proteins, molecular chaperones Cytoplasmic proteins that are involved in protein kinesis and repair, like protein folding, translocation and disaggregation. Important adaptive response found in all species  Heat shock proteins; HSP 2 families: – Produced always at low levels; HSP60, 90 – Produce under stress; HSP 70 HSP induced after injurious stimuli leads to refolding denatured proteins before causing death. If not responding, the protein is directed to bind with ubiquitin-proteasome pathway, leading to degradation. Lewy bodies and Mallory bodies are examples. Heat Shock Proteins; HSP Cell damage 2  Mechanisms of cell injury What are the general principle? The cellular responses to injurious stimuli depend on: the type, duration, and severity of injury. Consequences of an injurious stimulus depend on the type, status, adaptability & genetic make up of the cell.  Mechanisms of cell injury The main targets for the injury are: Ø Cell membrane, ionic and osmolarity homeostasis. Ø Mmitochondrial aerobic respiration (ATP) Ø Protein synthesis Ø Genetic apparatus (DNA)  Mechanisms of cell injury Regardless of the target that was initially attacked the different components are integrated in a way, that secondary effects will occur, and other components will be affected.  Mechanisms of cell injury Chronologically cell injury will follow - Loss of function (cell is viable), reversible - Cell death, irreversible 1. Biochemical changes (Enzymes of organs go to the blood) 2. Ultrastructural changes (I will use electron microscopy, details of cells “Mitochondria & Ribosome” 3. Light microscopic changes (Cell membrane, cytoplasm, nucleous) 4. Gross “macroscopic” changes  General biochemical mechanisms: 1. Mitochondrial damage and ATP depletion: Mitochondrial damage either directly or indirectly will lead to loss of ATP production. This will lead to loss of the function of cell organelles which are all dependent on the supply of the ATP  Mitochondrial damage Affection of the mitochondrial membrane by (1) Ca Phospholipases (2) oxidative stress This will lead to the formation of high conductive channels in the inner mitochondrial membrane. (mitochondrial permeability transition). Loss of the proton gradient across the mitochondrial membrane, and escape of cytochrome-C, initiating apoptosis. Mitochondrial damage  General biochemical mechanisms: 2. Oxygen changes: Whether through oxygen deprivation (hypoxia/ischemia), OR through the formation of free radicals.  General biochemical mechanisms: A. Hypoxic/ischemic injury: Hypoxia/ischemia will lead to decrease in the oxygen supply. The first system to be affected is the oxidative respiration by the mitochondria. This will lead to decrease in the ATP A. Hypoxic/ ischemic injury Cont. Loss of ATP dependent Na/K pump – Increase intracellular Na – Decrease intracellular K – Increase intracellular osmolarity – Acute cellular swelling Increase anaerobic glycolysis – Decrease glycogen – Accumulation of lactic acid – Lower PH Detachment of ribosomes, with loss of protein synthesis  Cont. All of these changes are reversible if the stimulus is removed. The changes will become irreversible if the stimulus continues.  B. Ischemia/reperfusion injury After restoration of the blood supply, a paradoxical tissue loss occurs, with more cells dying. This is explained on the basis of more influx of Ca into the partially damaged cells, inflammatory cells brought into the site of injury by blood, and production of free radicals by the partially damaged mitochondria. C. Free radical-induced cell injury Free radicals: Definition: unstable chemical species with a single unpaired electron in the outer orbital Either decay spontaneously or react with any other molecule to transfer the electron and change into a more stable form. Sources of free radicals: Produced normally in the cells: In normal respiration: Redox reaction Cell membrane e.g. NADPH oxidase Cytosol: Fenton reaction, xanthine oxidase. Peroxisomes: oxidase. ER: P450 oxidase. Inflammatory cells, in the lysosomes, myeloperoxidase, NO synthetase. Absorption of radiation, hydrolysis of water. Chemicals, CCl4, or drugs, Paracetamol, or O2 toxicity.  Targets for the free radicals lipid peroxidation of membranes, double bonds in the membrane polyunsaturated lipids are the targets. DNA fragmentation, due to reaction with thymine. Cross linking of proteins and fragmentation, due to sulfhydryl- mediated protein cross-linking.  Protection mechanisms Spontaneous decay. Superoxide dismutase (SOD), in the cytoplasm and mitochondria  Protection mechanisms: Glutathione peroxidase, in the cytoplasm and mitochondria.  Protection mechanisms: Catalase, in the peroxisomes Transport proteins, Ferritin, ceruloplasmin. Antioxidants: vitamin E/C/A They either block the formation, or savage the ones that are formed Summary of free radicals  Cell injury 3. Defects in plasma membrane permeability: Whether direct from the injurious stimulus or indirect, like 2ry effect after ATP depletion, or influx of calcium into cells. This will lead to break of the concentration gradient of the metabolites between the intra and extracellular environment.  Cell injury 4. Loss of calcium homeostasis: Free intracellular Ca concentration is 10000 less than extracellular concentration; this is achieved through an ATP-dependent pump with sequestration of calcium within the mitochondria and ER, and by binding to Ca-buffering proteins.  Cell injury With injury, influx of Ca into the cell, increase Ca concentration and activation of enzymes. Calcium is very important, since it acts as secondary messenger for the activation of different enzymes within the cell cytoplasm, like protein kinase, leading to loss of the integration of the cell. Calcium homeostasis  Cell injury 5. Chemical injury: Direct combination with a critical molecule of cell component. Activation of an inactive chemical.  Activation of an inactive chemical through the P-450 in the SER in the liver. This is followed by changing into free radicals CCl4 P-450/liver CCl3 free radical. This leads to membrane peroxidation, decrease protein synthesis, accumulation of fat, with fatty liver resulting.  Types of cell injury Reversible cell injury/sublethal cell damage Morphology: Remember the sequence of events; loss of function, ultrastructural, microscopic, macroscopic changes  Reversible cell injury Ultrastructural features: Plasma membrane alternation: blebs, loss of microvilli, loosing of intracellular attachment Mitochondrial alternation earliest manifestation of sublethal injury swelling, appearance of phospholipid rich amorphous densities  Reversible cell injury Dilation of endoplasmic reticulum loss of the ribosomes, and dissociation of polysomes Nuclear alternation Reversible cell changes Light microscopic changes: cell swelling (hydropic changes or vacuolar degeneration): universal to all cell types loss of ionic and fluid homoeostasis distended and punched out segments of ER cells show clear vacuoles in the cytoplasm  Reversible cell changes Fatty changes: Specific to cells dealing with fat metabolism, liver and heart Lipid vacuoles in the cytoplasm  Reversible cell changes Macroscopic changes; gross features: Increase in the weight of the organ Pallor of the organ  Types of cell injury Irreversible cell injury: “lethal damage” General pathways: excessive damage to all membranes, cytosolic and organelles Calcium is a potential mediator of irreversible cell death. Increase intracellular Ca content from the intracellular compartments, with activation of the different enzymes  Types of cell injury - Irreversible cell injury One of the earliest manifestations of irreversible cell injury is the vacuolization of the mitochondria, and the accumulation of amorphous, calcium-rich densities in mitochondrial matrix - Affection of the oxidative Phosphorylation, decrease ATP - Leakage of proteins and cellular constituents. This forms the basis for blood testing.  Irreversible cell injury Leakage of digestive enzymes from lysosomes. With the low pH, hydrolases are activated. They begin to digest the cell components. Autolysis: if the cells are digested by their own enzymes Heterolysis: if the cells are digested by lysosomes from other cells  Irreversible cell injury Nuclear changes: pyknosis, karyolysis, karyorrhexis Dead cells are eventually replaced by “myelin figures”. These are either phagocytosed or degraded into fatty acids, with deposition of calcium salts on top.  Mechanisms of irreversible injury 2 phenomena characterize irreversibility Inability to reverse mitochondrial dysfunction Development of profound disturbances in the membrane This is the VITAL step at which “No Return” issues  Irreversible cell injury Cell membrane damage: Progressive loss of membrane phospholipids. This caused by activation of phospholipases by Ca, and decrease synthesis of proteins Cytoskeletal abnormalities. Loss of the anchoring filaments between the cytoplasm and the cell membrane. So the cell membrane becomes loose and susceptible to rupture. Toxic oxygen radicals. This leads to peroxidation of the membranes. Lipid breakdown products. These act as detergents on the membranes.  Morphology of irreversible cell injury: Necrosis: The morphological correlate of irreversible cell injury Defined as the sequence of morphological changes that follows cell death in living tissue These morphological changes require hours to develop. They can’t be detected instantly  Morphology of irreversible cell injury: This morphological appearance is the sequence of 2 concurrent processes Enzymatic digestion of proteins Denaturation of proteins  Ultrastructural morphological changes: Defects in cell membrane Mitochondrial swelling and large densities Swelling of the ER and detachment of ribosomes Appearance of myelin figures Rupture of lysosomes  Light microscopic features Changes in the cytoplasm Acidophilia of the cytoplasm (Pink staining) Binding of eosins to denatured proteins Loss of basophilia from the loss of RNA Glassy cytoplasm: Loss of glycogen Vacuolated cytoplasm: Degeneration of organelles Calcification of cells  Light microscopic features Changes in the nucleus : Pyknosis: increased basophilia due to shrinkage of the nucleus Karyorrhexis: fragmentation of the pyknotic nucleus by nucleases Karyolysis: loss of the basophilia of the chromatin, 2ry to DNAase activity. 1-2 days following death, the nucleus disappears completely  Light microscopic features: Coagulative necrosis: Defined as death of cells with preservation of the basic structural outlines of the coagulated cells, with preservation of the general tissue architecture  Coagulative necrosis The most common type of necrosis Protein denaturation overcomes enzymatic digestion Seen in most organs after hypoxia/ischemia except brain Gangrenous necrosis: ischemic Coagulative necrosis of limb  Light microscopic changes Liquefactive necrosis: Defined as necrosis with complete digestion of the cells with obliteration of the normal architecture Enzymatic digestion overcomes the denaturation  Liquefactive necrosis 2 situations hypoxic/ischemic injury of the brain bacterial/fungal infection, with accumulation of WBCs and release of enzymes Wet gangrenous necrosis: ischemic Coagulative necrosis with superimposed bacterial infection  Light microscopic changes Caseous necrosis: Special type of necrosis, seen with tuberculus infection Grossly: cheesy white appearance to the necrotic focus Microscopically: the necrotic focus is composed of structureless amorphous granular debris  Light microscopic changes Fatty necrosis Special type of necrosis with focal areas of fat destruction Seen with acute pancreatitis, due to release of enzymes from the injured pancreas Grossly: fat saponification: visible whitw chalky areas Microscopically: shadows of cells with calcification Mechanisms of Cell Injury Normal Adaptation Heart Hypertrophy 2 -3 min 30 min 2 -3 hours 6 -12 h Apoptosis: Programmed cell death Dr. Dala Daraghmeh Ph.D pharmacology, Pharm.d Email: [email protected]  Apoptosis A distinctive type of cell death, where the cell commits suicide. Physiological or pathological: 1.Programmed destruction of cells during embryogenesis 2.Hormone-dependent physiological involution e.g. endometrium 3.Cell deletion in proliferating tissues e.g. epithelial cells of GIT  Apoptosis 4. Immune cell death e.g. autoreactive T- lymphocytes, cell death induced by T-cells in virally infected cells. 5.Mild injurious stimuli e.g. mild thermal, radiation, cytotoxic treatment. 6.Elimination of neoplastic cells in tumors. 7.Death of neurons in disease processes e.g. Alzheimer disease.  Mechanisms of apoptosis The main players are cytosolic proteins called Caspases and mitochondrial proteins called BCL-2 family.  Caspases: Enzymes which are present in the cytoplasm and are key players in apoptosis They are called caspases from C; from cysteine active site, “asp”; from cleavage after aspartic acid residue. Found in an inactive form in the cytoplasm.  Caspases: There are 2 types: – Initiators: signaling of these caspases results in commitment of cells to apoptotic cell death. These are found in certain cell types. – Effecters: these are proteases which bring about the structural degradation of the cells to give the classical morphology. They are present in all cell types. Mitochondrial proteins; BCL-2 family factors that influence mitochondrial membrane permeability and are important players in regulating apoptosis in the cells. Mitochondrial proteins; BCL-2 family stimuli like toxins, radiation, anoxia will open permeability transition pore complex (PTPC), or mega channels, which will release material mainly cytochrome-C from the mitochondria to cytosol. Cytochrome-C will bind to Apaf “pro-apoptotic protease- activating factor” and activate effecter caspases. Mitochondrial damage can cause apoptosis Mitochondrial proteins; BCL-2 family BCL-2 family are group of proteins that either suppresses apoptosis, like BCL-2 and BCL-XL, or enhances apoptosis like Bax/Bad. BCL-2 protects from apoptosis by stabilizing the mitochondrial membrane, thus preventing increase permeability, by binding and sequestering cytochrome-C, and stabilizing proteins like the Apaf, thus preventing its activation. Mechanisms of apoptosis  Mechanisms of apoptosis 1.signaling: This can be intrinsic like lack of growth factor, ligand-receptor interaction, release of granzyme from cytotoxic T-cells, radiation  Pathways for apoptosis 2. control and integration: Proteins that are mediators between signaling and execution Direct specific adaptor proteins and initiators caspases Regulation of mitochondrial outer membrane permeability with the release of cytochrome-C that can bind to Apaf-1, leading to activation of caspases. At this stage, the BCL-2 family plays its role  Pathways for apoptosis 3.execution: Activation of cytosolic enzymes leading to the morphological changes of apoptosis – Caspases: responsible for protein cleavage. key players in the process of apoptosis. under normal conditions they are suppressed.  Execution – Transglutamases: cross-linkage of proteins, so the cells are acidophilic and rigid. – Endonucleases: Fragmentation of the DNA at regular intervals, that are 180- 200 BP in length (nucleosomes) This is responsible for the laddering of the DNA by agarose gel electrophoresis. This laddering is characteristic of apoptosis but not pathognomonic. In contrast; DNA fragmentation is random in necrosis Apoptosis. Laddering of the DNA on agarose gel electrophoresis mediated by endonucleases.  Pathways for apoptosis 4.Removal of dead cells The apoptotic cells will be fragmented forming apoptotic buds (fragments of cytoplasm and some organelles and nuclear material). This process is associated with the expression of new surface ligands (phosphotidylserine). These are recognized by macrophages and adjacent cells, which are then engulfed and removed without inflammation. Apoptosis, morphology normal Apoptotic buds Apoptotic body removed  Morphology Difficult to appreciate histologically Single cells or groups of cells The cells are not surrounded by inflammatory cells Rapidly removed by fragmentation and engulfment by cells Features of coagulative necrosis versus apoptosis  Intracellular accumulation Accumulation of abnormal amounts of various substances within the cytoplasm or the nucleus. General pathways for intracellular accumulation Abnormal metabolism of substances. Defective folding and transport of proteins, alpha-1 antitrypsin deficiency. Genetic or acquired lack of enzyme, storage diseases. Accumulation of exogenous indigestible material. General pathways for intracellular accumulation  Fatty changes Defined as abnormal accumulation of triglycerides within parenchymal cells. Liver is the most common organ affected, but heart, skeletal muscles and kidney may be affected. As a general role, fatty changes are reversible.  Fatty changes Causes of fatty changes: – Toxins: alcohol is the most common cause. – Protein malnutrition: due to decrease in the synthesis of apolipoproteins. – Diabetes mellitus. – Obesity. – Anoxia and starvation.  Cholesterol and cholesterol esters Mainly accumulates in macrophages, leading to the formation of foam cells. Xanthoma cells are lipid-laden macrophages within the dermis in the skin. Causes of fatty changes in the liver  Proteins Less common than lipid accumulation. Reversible process. Russell bodies; accumulation of newly synthesized immunoglobulins within the RER in plasma cells. Mallory bodies; accumulation of eosinophilic intracytoplasmic inclusions in liver cells in association with alcohol.  Glycogen In diabetes mellltus; glycogen accumulates in renal tubular epithelium, cardiac myocytes, and beta cells of the Islets in the pancreas. Glycogen storage diseases are other examples.  Pigments. Colored substances that are either exogenous or endogenous. Carbon is the most common exogenous pigment. In the lung and the hilar lymph nodes carbon aggregates are called anthracosis. Endogenous pigments include lipofuscin, melanin, and hemosiderin.  lipofuscin “Wear and tear pigment”. Brownish-yellow granules. If apparent grossly, it will cause “brown atrophy”.  Melanin Accumulates in skin in inflammatory conditions.  Hemosiderin Hemoglobin derived golden-yellow pigment. Detected by special stain called “Prussian blue”.  Hemosiderin Hemosiderosis: accumulation of excess iron within macrophages. Hemochromatosis: a genetic defect with accumulation of iron within parenchymal cells in the liver, pancreas, heart and endocrine organs, “bronze diabetes”.  Pathological calcification Definition: abnormal deposition of calcium salts, together with smaller amounts of iron, magnesium and other minerals. Types of pathological calcification: – Dystrophic calcification. – Metastatic calcification.  Dystrophic calcification Deposition of calcium on dead or dying cells. Normal levels of serum calcium. Associated with organ dysfunction. Grossly appears as fine white granules. Microscopically: intracellular or extracellular basophilic deposits. Dystrophic calcification in aortic valve  Dystrophic calcification Involves two steps: – Initiation: Extracellular initiation: occurs on membrane bound vesicles derived from degenerate cells. Intracellular initiation: occurs in the mitochondria of dead or dying cells. – Propagation.  Metastatic calcification Deposition of calcium in normal tissue in the presence of hypercalcemia. Causes of hypercalcemia: – Increased secretion of parathyroid hormone. – Destruction of bone by tumors. – Vitamin-D related disorders. – Renal failure.  Metastatic calcification Affects mainly the interstitium of blood vessels, kidneys, lungs, and gastric mucosa. Dose not generally cause clinical dysfunction, unless the process is severe.