Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Zagazig University, Faculty of Veterinary Medicine, Department of Pathology, Egypt Telephone: +201224067373. e.mail: mohamedelariny@yahoo.com
Cellular Adaptation, Injury and Death By Prof. Dr. Mohamed Hamed Mohamed Professor of Pathology
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Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Cellular Adaptive, Injury and Death Normal cells are able to alter their function in response to modest stress and maintain homeostatic control. Excessive physiologic stress or pathologic stimuli (injury) result in adaptation. Definition: Adaptations are reversible functional and structural responses to more severe physiologic stresses and some pathologic stimuli, during which new but altered steady states are achieved, allowing the cell to survive and continue to function. Cellular response to stress and injurious stimuli: it includes i-Reversible injury: denotes pathologic cell changes that can be reversed (normal cellular function restored) if the stimulus is removed and/or the injury is mild. ii-Irreversible injury: occurs when stressors exceed the capacity of the cells homeostatic mechanism to adapt and result in permanent pathologic changes that result in decreased cell function and may cause cell death. Death may occur through two mechanisms: necrosis or apoptosis.
Fig (1): Stages of the cellular response to stress and injurious stimuli.
Cellular Adaptation The cells make adjustments with the changes under stress (adapt). Broadly speaking, such physiologic and pathologic adaptations occur by: i-Decreasing or increasing their size and number (atrophy, hypertrophy, hyperplasia).
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Cellular Adaptation, Injury and Death, Gangrene and PM Changes
ii-By changing the pathway of phenotypic differentiation of cells (metaplasia and dysplasia). In general, the adaptive responses are reversible changes.
Atrophy Definition: It means reduction of the number and size of cells, tissues and organs in living organism characterized by decrease or stopping their function. Causes and types of atrophy: A-Physiologic atrophy: It is a normal process of aging in some tissues: 1-Atrophy of lymphoid tissue in lymph nodes, appendix and thymus. 2-Atrophy of gonads after the mating seasons and menopause. 3-Atrophy of brain at senility. 4-Atrophy of bones in old age. B. Pathologic atrophy: It may be general and local. I-General atrophy: It is observed in cachexia due to i-Neoplasms and chronic diseases. ii-Starvation. iii-Injury of hypophysis (endocrine cachexia). iv-Injury of hypothalamus (cerebral cachexia). II-Local atrophy: It has several types: 1-Ischemic atrophy develops due to insufficiency of the blood supply. Hypoxia stimulates of the proliferation of fibroblasts and forms sclerosis. For example: small atrophic kidney in atherosclerosis of renal artery, atrophy of brain in cerebral atherosclerosis. 2-Disuse atrophy (dysfunctional) develops due to reduction of the function of organ: atrophy of muscles due to immobility, atrophy of the pancreas in obstruction of pancreatic duct. 3-Neuropathic atrophy due to interrupted nerve supply: poliomyelitis, motor neuron disease, nerve section, and inflammation of facial nerve. 4-Endocrine atrophy: hypopituitarism may lead to atrophy of thyroid, adrenal and gonads; hypothyroidism may cause atrophy of the skin and its adnexal structures. 5-Pressure atrophy: compression of spine by tumor in nerve root, compression of skull by meningioma arising from pia-arachnoid, compression of sternum by aneurysm of arch of aorta, compression of renal tissue by dilated renal pelvic in hydronephrosis, compression of brain tissue by dilated ventricles in hydrocephalus. 6-Atrophy due to chemical and physical influences: For example: action of the radiation lead to atrophy of bone marrow and genital organs. 3
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
7-Idiopathic atrophy: myopathies, testicular atrophy. Classification of atrophy according to special accompanying features: 1-Simple atrophy: No accompanying changes. 2-Fatty Atrophy: The missing cells are replaced by adipose tissue. 3-Fibrous (Fibrotic or Scirrhous) Atrophy: The missing cells are replaced by fibrous tissue. 4-Pigmented Atrophy (Brown Atrophy of Heart): Deposition of lipochrome pigments around the poles of muscular nuclei. Macroscopic Pictures: 1-The organ is small in size and weight. 2-The color of organ is darker. 3-The capsule of the organs is undulating or wrinkled. 4-A translucent gelatinous material replaces the adipose tissue. Macroscopic Pictures: 1- The number and size of the cells appear smaller. 2-In atrophic spleen; the trabeculae appear larger. 3-In atrophic kidney; the glomeruli appear numerous than normal. 4-In atrophic muscles; the nuclei seem to be more numerous than normal with more lipochrome pigments in cytoplasm NB: Hypoplasia: It is failure of an organ or tissue to reach to its normal mature size. It is mostly hereditary. Macroscopic Pictures: 1-The organ is small in size and weight. 2-The color of organ varies from pale to normal. 3-The capsule of the organs is tense. Macroscopic Pictures: 1- Decrease in the number of the cells. 2-These cells are ill-differentiated (not similar to the normal). 3-C.T. and adipose tissue replaced the failed cells.
Hypertrophy Definition: It refers to an increase in the size of parenchymal cells resulting in enlargement of the organ or tissue, without any change in the number of cells. Mechanisms of hypertrophy Hypertrophy of tissue arises due to increase of size of functional cells. Thus, the hypertrophied organ has no new cells, just larger cells. NB: Hypertrophy of tissue arises due to increase of number of functional cells (hyperplasia). 4
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Hypertrophy of cells arises due to both increase of size of functional cells and increase of number of ultrastructural elements. 1-True Hypertrophy: It is due to the synthesis of more structural components 2-False hypertrophy: It is the increase of the size of organs due to growth of connective tissue, accumulation of the fluid or fatty tissue. It results in atrophy of organ (hydronephrosis, hydrocephalus, obesity of heart). Types of Hypertrophy: I-Physiological (Hormonal) Hypertrophy: as enlarged lactating mammary gland and testis in birds and some animals in mating seasons or working. II-Pathological Hypertrophy: It is either A-Compensatory Hypertrophy: usually occurs in paired organs as kidneys. When loss of one kidney; the other is gradually enlarged to compensate the function of the other kidney B-Adaptive Hypertrophy: myocardial hypertrophy due to back pressure due to stenosis, hypertension undergoes enlargement of myocardium. NB: According to stage of adaptation the myocardial hypertrophy have two types: 1-Concentric Hypertrophy: the musculature is clearly enlarged, but the chambers of the heart are not dilated (clinically, no insufficiency). 2-Eccentric Hypertrophy: the myocardium is enlarged but chambers of the heart are dilated. This leads to hemodynamic disorder with cardiac insufficiency (myogenic dilation). Macroscopic Pictures: 1-The affected organs are enlarged and heavy. 2-Normal color and consistency. Microscopic Pictures: 1-The cells are large with increased the amount of the cytoplasm and cellorganelles.
Hyperplasia Definition: It is an increase in the number of parenchymal cells resulting in enlargement of the organ or tissue. Quite often, both hyperplasia and hypertrophy occur together. Causes: 1-Chronic irritation. 2-Deficiencies. 3-Endocrine imbalance. 1-Chronic Irritation: 5
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
i-Mechanical: Continuous irritation of skin to form keloid. ii-Infections: A-Parasitic infection: as Coccidiosis in the bile ducts of rabbits. B-Viral Infection: as Papilloma virus, Duck viral hepatitis and Pox. iii-Toxins: as Seneca-poisoning and Aflatoxins cause hyperplasia in the bile ducts. 2-Deficiencies: A-Iodine deficiency: hyperplasia in the lining epithelium of the thyroid glands. B-Vitamin A deficiency: hyperplasia of the epithelium of skin and esophagus. 3-Endocrine imbalance. Hyperplasia of the prostate due to imbalance between estrogen and testosterone in old age. Types of the Hyperplasia: 1-Hemopoietic hyperplasia (leukocytosis, neutrophilia,‌) 2-Epithelial hyperplasia (as in pox) 3-Lymphoid hyperplasia (in lymphoid tissue). 4-Myloid hyperplasia (in bone marrow). Macroscopic pictures: 1-The affected organs is enlarged and heavier in weight. 2-The capsule is tense. 3-The color become pale than normal. 4-The cut surface is bulged. Microscopic pictures: 1-Increase the number of the cells forming papillary projections in the lumen. 2-The cells are well differentiated (similar to the normal). 3-The causative agents may be seen as stages of coccidia in the epithelium lining of bile duct of rabbits. Remarks: Acanthosis: It is the thickening of the epidermis due to hyperplasia in stratum spinosum. Hyperkeratosis: It is the thickening of the epidermis due to hyperplasia in stratum cornium with no evidence of nuclei. Parakeratosis: It is the thickening of the epidermis due to hyperplasia in stratum cornium with presence of nuclei.
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Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Metaplasia Definition: It is a reversible change of one type of basic tissue to another type of the same basic tissue (in adult). Metaplasia is broadly divided into 2 types: A-Epithelial metaplasia: This is the more common type. The metaplastic changes are either patchy or diffuse and usually result in replacement by stronger but less wellspecialized epithelium. i-Squamous metaplasia: Such as changes from pseudostriatified columnar of the bronchial epithelium to stratified squamous epithelium due to smoking. ii-Goblet cell metaplasia: in catarrhal inflammation or mucinous degeneration, the columnar epithelium transformed into goblet cells to produce the mucin. B-Mesenchymal or C.T. metaplasia: Less often, there is transformation of one adult type of mesenchymal tissue to another. Osseous metaplasia: The fibrous connective tissue transformed into cartilage or bone. It is usually seen in tumor of mammary glands of bitch (mixed tumor). Causes: 1-Vitamin A deficiency induces squamous metaplasia of respiratory and salivary epithelium. 2-Chronic Irritation for long period. 3-Senility as change of the simple columnar epithelium of endometrium into squamous epithelium. 4-Hormonal disturbances. Significance: The metaplasia has a tendency to induce neoplasia.
Dysplasia “disordered cellular development� Dysplasia = lack of formation (Precarcinogenic changes). It refers to alteration in shape, size and organization of cells. It may occur during fetal development or in adult tissues. Dysplasia characterized microscopically by abnormal orientation of cells, variation in size and shape of cells and nuclei. It include: i-Hyperplasia of epithelial layers. ii-Disorderly arrangement of cells from basal layer to the surface layer. iii-Cellular and nuclear pleomorphism. iv-Increased nucleocytoplasmic ratios. v-Nuclear hyperchromasia. 7
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
vi-Increased mitotic activity. The two most common examples of dysplastic changes are the uterine cervix and respiratory tract.
Fig (2): Different types of cellular adaptation. Remarks: The disturbances in development.
Disturbance in Development Congenital Abnormalities It includes either: I-Anomalies II-Monsters (Monstrosity) I-Anomalies: It is a disturbance of development that involves an organ or a part of it. Classification of Anomalies: A-Arrest of Development: 1-Agenesis: (not produced). It is the complete failure of an organ or part of it to produce during embryogenesis with absence of primordium (intrauterine). 2-Aplasia: (not formed). It is the complete failure of an organ or part of it to be formed during embryogenesis with presence of primordium. 3-Hypoplasia: It is failure of an organ or tissue to reach to its normal mature size. It is mostly hereditary. 4-Fissures (Schisis): as harelip, platoschesis, schistothorax,‌ 8
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
5-Fusion of paired organs: as in kidneys (horseshoe kidney), in eyes (cyclopia). Examples for arrest of development: Acrania: It is absence of the bone of skull. Agnathia: It is absence of the lower jaw. Abrachia: It is absence of forelimb. Adactylia: It is absence of digits. Atrasia ani: It is absence of anal opening. B-Excessive development: 1-Congenital hypertrophy: as hemihypertrophy overgrowth of one side of the body or a part of it. 2-Increased number of a part: as poly-odontia, mastia, dactylia, thelia.. C-Displacement during development: 1-Displacement of organs: as ectopia cordis. 2-Displacement of tissue: as teratoma, dermoid cyst,‌ D-Persistence of fetal structures: as foramen ovale, ductus arteriosus, urachus,.. E-Fusion of sexual character: as hermaphrodite, free martin. II-Monsters (Monstrosity): It is a disturbance of development that involves several organs and causes great distortion of the individual. Types of Monsters: 1-Compound Monsters: fetus with some duplication of parts. 2-Double (twin) Monsters: fetus arising from a single ovum but with duplication of head, trunk or limbs. 3-Triple Monsters: fetus with triplication of body parts. 4-Parasitic Monsters: Imperfect fetus (small and ill developed) unable to exist alone and attached to an autistic partners. 5-Autistic Monsters: fetus capable of independent life, the circulation of which supplies nutrition to its parasitic partners. Some medical terms: Free Martin: It is a sterile female with rudimentary female genital system. Twins of both sex share in a chorion and placenta. Male sex hormone appears earlier than that of the female and depresses the growth of genital tract of female (White heifer). Brachium = Arm. Pagus = Fixed or connected. Prosopo = Face. Rachus = Spinal column. Pygo = Sacrum (buttocks). 9
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Cyst: It is a cavity bounded by a wall and contain fluid. Types of the cysts: A-True Cyst: cysts with its fluid content secreted from its epithelial lining as retention cysts (Ranula). B-False Cyst: Its fluid content collected as a result of some degeneration within a solid mass as Hematoma.
Differences between Hypoplasia and Hyperplasia Hypoplasia
Atrophy
-The capsule is Tense
-The capsule is undulating or wrinkled
-It consists of ill-differentiated cells (not similar to the normal)
-Well-differentiated
-C.T. and adipose tissue replaced the failed cells
-The degenerated or necrotic cells is replaced by C.T. or adipose tissue
-No inflammatory cells
-Presence of inflammatory cells
Differences between Hyperplasia and Neoplasia Criteria
Hyperplasia
Neoplasia
1-Cause
Known
Unknown
2-Regression after remove the cause
Occur
Not occur
3-Morphology of cells
Typical
Atypical
4-Organization of cells
Present
Variable
Usually multiple
Single
6-Nucleus
Normal
Mitoses
7-Pleomorphism
Absent
present
5-Tissue involved
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Cellular Adaptation, Injury and Death, Gangrene and PM Changes
CELLULAR INJURY AND CELLULAR DEATH Causes of cellular injury It classified into two large groups: 1-Genetic causes: 2-Acquired causes: i-Hypoxia and ischemia. ii-Physical agents (mechanical trauma, thermal trauma, ultraviolet and ionizing radiation, rapid changes in atmospheric pressure). iii-Chemical agents and drugs. iv-Infectious agents. v-Immunologic agents. vi-Nutritional derangements. vii-Physiologic factors.
Acute Cell Injury A-Reversible cellular injury: is characterized with the ability of the cell to return to its normal state after withdrawal of an acute stress. Reversible injury is manifested with hydropic swelling of the cell (cellular edema), dilation of endoplasmic reticulum, and detachment of ribosomes from the granular endoplasmic reticulum, dissociation of polysomes into monosomes, mitochondria swelling and enlargement, blebs of plasma membrane, nucleolar alterations with disaggregation of granular and fibrilar elements. B-Irreversible cellular injury (Cellular death): as necrosis and apoptosis.
Morphogenetic mechanisms of intra- and extracellular accumulations Mechanisms of the development of intra- and extracellular (stromal) degenerations (dystrophies) are the followings: i-Infiltration: It is excessive accumulation (deposition) of metabolites into the cells and extracellular matrix. ii-Decomposition (phanerosis): It is the disintegration of membranous structures of the cells and extracellular matrix. iii-Perverted synthesis: It is a synthesis of abnormal substances in the cells and tissues. iv-Transformation: It is the formation of one type of metabolism’s products from common initial substances for proteins, fats and carbohydrates.
Cellular death It is defined as that point when cell injury becomes irreversible (point of no return). For every cell, there is a time to live and a time to die. There are 2 ways in which cells die: 11
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
I-Death by Injury: Cells that are damaged either by i-Mechanical damage.
ii-Exposure to toxic chemicals.
Mechanisms of Damage: 1-Injury mitochondria decrease the energy production (ATP) decrease the ability of the cell membrane to control the passage of ions and water cell swelling and then necrosis. 2-The cell contents leak out leading to inflammation of the surrounding tissue “Accidental cell death or necrosis”. II-Death by Suicide: Cells that are induced to commit suicide. Mechanisms of Damage: 1-Cell shrinkage with intact cellular membrane. 2-Develop bubble-like blebs on their surface. 3-Degradation of nuclear chromatin by endonuclease (DNase). 4-Breakdown of mitochondria with release of cytochrome C (reductase or oxidase). All of these (1-4) lead to “Apoptosis or programmed cell death”. The appearance of the cell death depends on the predominant process activated: i-Enzymatic degradation (autolysis/heterolysis). ii-Protein denaturation. NB: -The morphological irreversible cell-injury includes: i-Pyknosis ii-Karyorrhexis iii-Karyolysis Iv-Mitochondrial dense bodies (calcium) v-Plasma blebs
Types of Cell Death Criteria
Necrosis (Oncosis)
Autophagy
Apoptosis
Ontosis
Key Target
Cell membrane ATP production
Autophagosomes
DNA
Plasma membrane lysosome
Energy dependent
No
Yes
Yes
Yes
Protein synthesis
No
Yes
Yes
Yes
Inflammatory response
Yes (Neutrophils)
Minimal
No
No
Morphology
Areas or groups of cells, cell swelling, pyknosis
-Single cells -Lysis
Single cell, shrinkage, pyknosis
-Single cells -Cell-in-cell
NB: Somatic Death: refers to death of entire body, there is cessation of all body function. The absence of heart beat, pulse, respiration and other reflexes. Necrobiosis: refers to death of cells at the end of their life span within the living body as erythrocytes, leukocytes, epithelium (apoptosis). 12
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
I-Programmed Cell Death Apoptosis It is an important mode of cell death induced by suicide program through activation of some of its enzymes capable of degrading the cells' nuclear DNA and nuclear and cytoplasmic proteins. A-PCD is as needed for proper development as mitosis (Physiological). B-PCD is needed to destroy cells that represent a threat to the integrity of the organisms (Pathological) and includes: 1-Cells infected with viruses. 2-Cells of the immune system. As Cell-mediated immune responses. the effector cells must be removed to prevent them from attacking body constituents. Defects in the apoptotic machinery are associated with autoimmune diseases as lupus erythematosus. 3-Cells with DNA damage. Cells respond to DNA damage by increasing their production of P53 (a potent inducer of apoptosis) 4-Cancer cells. Radiation and chemicals used in cancer therapy induce apoptosis.
Morphological Features of Apoptosis: 1-Cell shrinkage: -Loss of surface contact as cell separates from its neighbors. -Loss of specialized membrane structures e.g. microvilli, desmosomes. -Organelles become tightly packed making the cytoplasm appear dense.
2-Chromatin condensation: -Chromatin condenses to the periphery of the nucleus forming crescents. -Nucleolus disintegration. -Loss of nuclear pores. -Nuclear fragmentation (karyorrhexis). 3-Cytoplasmic membrane blebbing (Zeiosis): with formation of apoptotic bodies containing cytoplasmic organelles and nuclear fragments. 4-Phagocytosis of apoptotic bodies: by neighboring cells or macrophages.
Biochemical Features of Apoptosis: 1-Protein cleavage by caspases, the central executioners of the apoptotic pathway accounts for the distinctive cytoplasmic and structural changes seen in apoptotic cells. 2-DNA breakdown by endonucleases triggered by caspase activity. 3-Phagocytic recognition by expression of surface markers on the apoptotic cell.
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Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Mechanism of Apoptosis: Two different mechanisms for apoptosis are recorded: I-Mitochondrial Pathway (Intrinsic): It includes A-Apoptosis Triggered by Internal Signals: -The mitochondria contain several proteins that capable of inducing apoptosis; including Bcl-2, cytochrome c, APaf-1 and caspase 9 besides the ATP (caspases cascade). i-Bcl-2 normally (antiapoptotic gene) present on the mitochondrial surface and bind to a molecule of apoptosis activating factor (Apaf-1). ii-At mitochondrial damage, the Bcl-2 and Apaf-1 release with releasing the cytochrome c. Caspase 9 + ATP
iii-Apaf-1 + Bcl-2
Apoptosome (apoptotic bodies). Cytochrome c
B-Apoptosis Inducing Factors (AIF) AIF is a protein normally located in the mitochondria and when the cell receives a signal telling it is a time to die, the AIF i-Releases from the mitochondria. ii-Migrate to the nucleus. iii-Binds to the DNA. iv-Triggers the DNA-damage and cell death (apoptosis).
II-Apoptosis Triggered by External Signals (Extrinsic or Death receptor pathway): Many cells expressed surface molecules that trigger apoptosis and called death receptors. Most of these receptors are member of TNF receptors or FAS (CD95). Binding between death activators (TNF-Îą and FASL) with their expressed receptors with activation of caspases 8 resulting in initiating caspases cascade and phagocytosis of the cells.
Stages of Apoptosis: 1-Signaling (initiation). 2- Control and Integration (progression). 3-Common-Execution Phase (Caspases). 4- Disposal or Removal Phase (phagocytosis).
1-Signaling (initiation): -Absence of cell survival signals as growth factor and extracellular matrix -Death activators (FASL and TNF-Îą) bind to death receptors (FAS and TNF). -DNA-damage with increase production of P53. -Cytotoxic T cells.
2-Control and Integration (progression): -Release of mitochondrial cytochrome C. 14
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
-Balance of pro-apoptotic and anti-apoptotic members of Bcl-2 family “overexpression of bcl-2 in B-cell lymphoma”. -Activation of P53 tumor suppressor gene “high percentage of tumor cells have mutant P53 and are defective in apoptosis” -Activation of caspases (by the previous: cytoch., Bcl, P53). -Activation of granzyme B direct caspase activation.
3-Common-Execution Phase (Caspases): -Activation of latent Caspases: (Proteases that degrade important proteins, have cysteine at the active site and target aspartate residues i.e. Caspase). -Caspases are activated from latent form to active form in a cascade of proteases. -Caspases activate latent caspase activated DNase (CAD) degrades DNA into "ladders". -Protein crosslinking occurs due to activation of transglutaminases. -Formation of Apoptotic bodies.
4-Disposal or Removal (phagocytosis) Phase: The apoptotic cells show several changes in their membranes that promote their phagocytosis by neighboring cells or phagocytes (macrophages). Moreover, apoptotic cells secret soluble factors that attract phagocytes.
Differences between Apoptosis and Necrosis Apoptosis
Necrosis
Physiological or pathological
Always pathological
Single cells
Sheets of cells
Energy dependent
Energy independent
Cell shrinkage
Cell swelling
Membrane integrity maintained
Membrane integrity lost
Role for mitochondria and cytochrome C
No role for mitochondria
No leak of lysosomal enzymes
Leak of lysosomal enzymes
Characteristic nuclear changes
Nuclei lost
Apoptotic bodies form
Do not form
Orderly DNA fragmentation (Ladder)
disorderly DNA fragmentation
Activation of Caspases (cascade)
No activation
Regulatable process
Not regulated
Evolutionarily conserved
Not conserved
Dead cells ingested by neighboring cells
Dead cells ingested by neutrophils and macrophages
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Cellular Adaptation, Injury and Death, Gangrene and PM Changes
II-Accidental Cell death Necrosis (Oncosis) It is a local death of cells or tissue in the living body. The necrosis is caused by the progressive degradative action of enzymes on the injured cells. After a cell die, lysosomes rupture and their hydrolytic enzymes are released. The release and activation of these enzymes are responsible for cell necrosis. NB: Necrotic cells are dead cells; but dead cells are not necessarily necrotic. Causes of Cell Injury and Necrosis: 1-Hypoxia or Ischemia (Hypoxic Cell Injury): Hypoxia rapidly leads to i-Decrease of ATP ii-Increase of Cytosolic Ca++. iii-Free radical formation. All of which cause cellular membrane injury. i-Decrease of ATP leads to: A-lose of most energy dependent processes as; -Protein synthesis -DNA replication B-Increase anaerobic glycolysis accumulation of lactic acid and decrease intracellular pH clumping of the nuclear chromatin and inactivation of nuclear RNA. C-Disturbance in Na+/K+ pump in the cell membranes resulting in entrance of the Na+ and water within the cell (cell swelling) rupture. ++ ii-Increase of Cytosolic Ca : A-Calcium enters the injured cells to precipitate the calcium phosphate on the internal cell membrane leading to activation of endogenous phospholipase which breaks down the phospholipids from the cell membrane and release unsaturated fatty acids cause further damage of cellular membrane. ++ B-Increase the Ca also activates proteases and endonucleases with reduction of ATP.
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Cellular Adaptation, Injury and Death, Gangrene and PM Changes -
-
iii-Free Radicals (O , OH , H2O2, ..): They attack lipid, protein and DNA. Free radical attack the cell membrane generated lipid peroxidation inducing damage the membrane and cell injury. Moreover, the free radicals act as source of oxidant which is severely cytotoxic. 2-Chemical Poisoning: It causes either: i-Damage of cellular membrane and mitochondria decrease ATP ii-Exogenous chemicals may be transferred to more reactive metabolites that liberate free radicals permanent membrane damage and cell death. 3-Microbial Agents: Injuries by microbes as viruses, bacteria, fungi and parasites. 4-Physical Agents: Trauma, cold, heat, prolonged pressure, … 5-Allergy and immunological: Such as type III hypersensitivity. 6-Lack of Nerve Supply: 7-Nutritional Imbalance A deficiency or excess of nutrients may results in nutritional imbalance.
Microscopic Changes of Necrosis: They include:
A-Nuclear Changes. B-Changes in the Cytoplasm C-Changes in the Whole Cell.
A-Nuclear Changes: 1-Pyknosis: The pyknotic nucleus is decreased in size (shrunken), round and homogenously dark blue to black (hyperchromatic) with lack nucleolus. These changes occur because the nucleic acid component of chromatin has been enzymetically stripped of the associated nucleoproteins so the nucleus is shrinked and more acidic (increase in affinity to basic dye). The elongated nuclei of connective tissue and muscle cells don’t become round; condensation of chromatin and hyperchromasia are seen. The necrotic neurons don’t become pyknotic and it firstly swollen and then fragmented. 2-Karyorrhexis: It is fragmentation of the chromatin into numerous small basophilic granules with ruptured (disappearance) of the nuclear membrane. 3-Karyolysis: It is dissolution or lysis of chromatin leaving a faint ghost of the nuclear membrane. The lysis is occurred by nuclease released from leaking lysosomes of dead cells. 4-Loss of the nucleus (Chromatolysis): It is complete absence of the nucleus, its chromatin and membrane.
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Cellular Adaptation, Injury and Death, Gangrene and PM Changes
B-Changes in the Cytoplasm: 1-Depletion of Cytoplasmic Glycogen: It is due to anaerobic glycolysis. Normally, the cytoplasm appears vacuolated due to dissolving the carbohydrate by water during histological preparation; but in dead cells, the cytoplasm appears homogenous due to loss of glycogen particles. 2-Increased Eosinophilia of Cytoplasm: The cytoplasm of necrotic cells is more eosinophilic than normal due to: A-Degradation of cytoplasmic RNA gives a degree of basophilia to the normal cytoplasm. B-Denaturation of cytoplasmic proteins give rise to polypeptide chains leads to increase number of reactive sites for eosin. 3-Cytoplasmolysis: It is complete disappearance of the cytoplasm.
C-Changes in the Whole Cell: They include: 1-Loss of cell outline: 2-Loss of differential staining: 3-Loss of cells:
Macroscopic Changes of Necrosis: It includes: 1-Loss of Color: 2-Loss of Strength: 3-Change in Odor: 1-Loss of Color: The necrotic tissue becomes pale (due to hemolysis of erythrocytes in necrotic areas and diffusion of normal pigments such as myoglobin in striated muscles). 2-Loss of Strength: The necrotic tissue has less tensile strength than normal due to “enzymatic digestion of cytoskeleton, cell membrane and intercellular connections�. The necrotic tissue may be friable (caseous necrosis), firm (coagulative necrosis) or liquid (liquefactive necrosis). 3-Change in Odor: Odors of putrefaction may be noticed from dead tissue invaded by saprophytic bacteria after gangrene or postmortem autolysis. This foul-smelling is due to release of hydrogen sulfide. 18
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
NB: Macro of necrosis Micro of necrosis 1-Grayish-white in color 1-Loss of cellular detail and tissue architecture 2-Friable in consistency. 2-Line of defense Types of necrosis: 1-Coagulative necrosis 2-Caseous necrosis 3-Liquefactive necrosis 4-Fat necrosis
Coagulative necrosis It is a local death of tissue in the living individual, which is characterized by maintenance of tissue architecture and loss of cellular details. It results from denaturation of cellular proteins proceeds degradation of hydrolytic enzymes (lysis). The coagulated tissue is slowly liquefied by heterolysis (by inflammatory cells or neutrophils).
Causes: 1-Local ischemia as infarction. 2-Toxic products of certain bacteria as Fusobacterium necropherus. 3-Chemical poisons as mercuric chloride. 4-Virus infection as FMD. 5-Mild burns. 6-Nutritional deficiency (Vit. E, Selenium) results Zenker's necrosis
Microscopic Picture: 1-Maintenance of tissue architecture. 2-Loss of cellular detail. 3-Few leukocytes may be seen.
Macroscopic Picture: 1-The necrotic tissue is gray or white in color 2-Firm in consistency. 3-Depressed under the level of surrounding tissue.
Caseous necrosis It is a local death of tissue in the living individual, which is characterized by loss of both tissue architecture and cellular details and the tissue, is replaced by eosinophilic and basophilic granular debris (resembling cottage cheese). This type of necrosis results from a mixture of coagulated protein and lipid, and usually associated with the death of macrophages and eosinophils or dehydration of pus (inspissated pus).
Causes: 1-Ovine caseous lymphadenitis. 2-Tuberculosis. 3-Mycotic infection as Aspergillosis. 4-Parasitic infestation as Histomoniasis. 19
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Microscopic Picture: 1-Loss of both tissue architecture and cellular details and the necrotic tissue represented by eosinophilic and basophilic granular debris. 2-Line of defense (consisting of inflammatory cells, fibrin threads and dilated blood capillaries).
Macroscopic Picture: 1-Yellowish, gray or white in color. 2-Friable, dry and slightly greasy without any cohesive strength (similar to cottage cheese). 3-Gritty sound may be felt during cut section due to calcification. NB: Caseous necrosis has a high tendency to dystrophic calcification.
Liquefactive necrosis It is a local death of tissue in the living individual, which is characterized by loss of both tissue architecture and cellular details and the tissue, is replaced by fluid. There are two principal sites of liquefactive necrosis: 1-Associated with “suppurative inflammation” due to presence of numerous neutrophils, which die to form pus cells and produce proteolytic enzymes to liquefy the necrotic tissue. 2-Associated with “the necrotic CNS” which rich in non-coagulable lipoidal material and poor in coagulable albumin encephalomalacia.
Microscopic Picture: I-In suppurative inflammation: 1-Loss of both tissue architecture and cellular details which replaced by structureless basophilic substance. 2-Line of defense between dead and healthy tissues (consists of dead and living neutrophils, fibrin threads and dilated blood vessels).
II-In CNS: 1-Presence of cavities (empty or contained pale eosinophilic material) which has frayed and irregular edges. 2-These cavities may be surrounded by inflammatory reaction (microglia).
Macroscopic Picture: 1-Pus of different colors and consistency are seen in suppurative inflammation. 2-Yellowis-white or opaque fluid in CNS. 3-If the process is still progress in CNS, cysts containing fluid are seen.
Fat necrosis It is the death of adipose tissue in the living individual. When adipose tissue undergoes necrosis, the fat is slowly decomposed into “fatty acids and glycerin”. The fatty acids combine with metallic ions (sodium, potassium and calcium) to form soaplike compounds. These compounds are not dissolved by fat-solvents during the histological preparation, hence the compounds persist. 20
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Causes and Types of Fat Necrosis: A-Pancreatic Fat Necrosis (Internal or Abdominal): It occurs only in the abdominal cavity as a result of the fat-splitting by the action of pancreatic lipase: Fat fatty acids + glycerin (absorbed by lymphatics). Na Na soap (blue). Fatty acids + K K soap (pink). Ca Ca soap (purple). This type is seen due to: 1-Injury to pancreas or its ducts. 2-Acute pancreatitis. 3-Rupture of pancreas or neoplasm. 4-Excessive fat diet which leads to pancreatitis.
B-Traumatic Fat Necrosis (External): It occurs in the subcutaneous and intermuscular fat. Where the “lipase-enzyme” is liberated from the connective tissue. This type is seen due to trauma.
Microscopic Picture: 1-The affected fat cells appear cloudy or replaced by acicular or crescentic crystals (soap). It may blue (Na), pink (K) or purple (Ca). 2-The nuclei of fat cells are pyknotic. 3-The necrotic area is surrounded by inflammatory reaction (macrophages, lymphocytes and giant cells). 4-No neutrophils are present due to acidic media (as caseous necrosis).
Macroscopic Picture: 1-The affected adipose tissue losses its shiny and become dull, white-chalky, opaque and granular. 2-The fat is not greasy. 3-Gritty sound may be felt during cut sections due to calcification. 4-Exudation of fluid may occur.
Zenker’s Necrosis It is a type of coagulative necrosis, associated with coagulation of protein of the sarcoplasm of striated muscles.
Causes: 1-Vitamin E deficiency (white-muscle disease). 2-Selineum deficiency. 3-Toxins of bacteria (clostridial disease as Blackleg).
Microscopic Picture: 1-Maintenance of the tissue architecture (muscle fibers are swollen, homogenous and more eosinophilic. 21
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
2-Loss of cellular detail (loss of both longitudinal and cross striations with loss of Cohenheim field). 3-Inflammatory cells among the necrotic fibers (line of defense).
Macroscopic Picture: 1-Grayish-white in color (flesh-fish like). 2-Friable in consistency.
Fibrinoid necrosis It is a local death of collagen fibers in living individual and characterized by injury and fragmentation of collagen fibers especially media of blood vessels.
Pathological Features: 1-Edema tends to separate the collagen bundles. 2-Increase mucopolysaccharide in the ground substance (homogenous bright pink staining material). 3-The collagen fibers are fragmented and transformed into stringy and more eosinophilic mass-like fibrin (fibrinoid necrosis). 4-Chronic inflammatory cells infiltration and fibrosis are seen at these areas.
Sequelae of necrosis I-Small area of necrosis: 1-Removed by macrophages. 2-Liquefied and absorbed by blood or lymph. 3-Desquamation and sloughing especially in the skin. 4-Regeneration in the epithelium (healing by first intention). 5-Organization by granulation tissue and scar formation. 6-Suppuration with abscess formation by invasion of pyogenic m.o.
II-Large area of necrosis: 1-Encapsulation by thick fibrous connective tissue. 2-Dystrophic calcification. 3-Gangrene if the necrotic tissue invades with putrefactive organisms. 3-Fatal if present in vital organs. 4-Cyst formation (liquefied and surrounded by ct. capsule. NB:
Cholesterol Clefts: 1-They occur as by-product of necrosis and appeared as empty spaces (containing crystals of cholesterol which dissolved by fat-solvents during histological preparation). 2-These spaces have characteristic shape (50-100 Âľ long and 5-10 Âľ thick flat and thin rhomboid plate). 3-This crystal comes from decomposed cytoplasm and membrane of dead cells. 4-They also found at the area of old hemorrhage, old abscess and Atheroma.
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Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Comparisons between Different Types of Necroses Criterion I-Micro: 1-T. architecture 2-C. details 3-Line of defense 4-Replacements
II-Macro: 1-Color 2-Consistency III-Causes IV-Tissue involved
Coagulative
Caseous
Liquefactive
Fat
+ + Coagulated eosino tissue
+ Gran eosino and basophilic debris
+ Structureless basophilic or cavities in CNS
+ Acicular crystals
-Grayish -Firm -Toxins, viral, nutritional -Any tissue and Zenker’s in Mm
-Yellowish -Friable -Dead macs, eosio and dry pus -Any tissue
-Colored pus -Liquid -Pyogenic m.o.
-Chalky-white -Firm -Lipase
-Any tissue
-Adipose tissue
III-Entosis It is cell internalize into their neighbors following its detachment. NB: Cannibalism can be either homogeneous or heterogeneous cell-in-cell structures, while Entosis is a homogeneous cell-in-cell phenomenon. The process of entosis is different from cannibalism in that entosis is a live cell invasion while cannibalism has no selectivity for dead cells or live cells. In the neoplasm of high malignancy revealed that the internalization of natural killer (NK) cells in tumor cells is a distinct type of cell-in-cell phenomenon that is different from cannibalism and entosis. i-Cell internalization occurs independent of apoptotic processes. ii-Cell-engulfment requires Actin, myosin II, Rho and Rock activity. iii-Rho and Rock are required in internalizing cells. iv-Cadherens are required for entosis. v-Adherens junctions track internalization. vi-Entosis results in lysosomal cell death. vii-Internalized cells can die by alternative mechanisms. viii- Internalized cells can be released.
IV-Autophagy It is digestion of cellular constituents by enzymes of the same cell. It has 4 phases: 1-Iduction (mTOR). 2-Phagosome formation (complex of Atg protein, in particular Atg 5 and Atg12 to recruit Atg8; Beclin-1/Atg14). 3-Fusion with lysosome. 4-Autophagosome breakdown (LAMP-2). 23
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
NB: i-Mammalian target of rapamycin (mTOR) is a serine-threonine protein kinase that regulates several intracellular processes in response to extracellular signals, nutrient availability, energy status of the cell and stress. mTOR regulates survival, differentiation and development of neurons. ii-Atg and Beclin-1 are autophagic protein regulate the mechanism. iii-LAMP-2: is lysosomal-associated membrane protein-2. It plays an important role in: i-protection of the lysosomal membrane from autodigestion. ii-Maintenance of the acidic environment of the lysosome. iii-Adhesion when expressed on the cell surface (plasma membrane). iv-Inter- and intracellular signal transduction. v-Protects cells from the toxic effects of methylating mutagens. vi-It has specific role in tumor metastasis.
Gangrene It is invasion and putrefaction of necrotic tissue by saprophytic bacteria.
Pathogenesis:
I-Primary Gangrene It occurs if the m.o. induce necrosis and putrefaction of the tissue e.g. clostridial diseases as blackleg.
II-Secondary Gangrene: It occurs if the necrotic tissue is invaded and putrefied by saprophytic bacteria. Gangrene External Internal (Dry) (Moist) Secondary (Ischemic or arterial occlusion)
Primary Secondary (Clostridial diseases)
Causes of Gangrene: It is the same as necrosis plus exposure to putrefactive bacteria. NB: The bacteria require moisture, nutrient (in blood) and warmness. There are three forms of gangrene: dry, moist and gas gangrenes.
1-Dry Gangrene Macroscopic Picture: 1-Greenish or black in color due to combination of H2S with iron to form iron sulphide (black) or Met-Hb to form sulph-Met-Hb (greenish). 24
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
2-Bad or fetid odor due to putrefaction and H2S production. 3-Dry (leather-like). 4-Contracted and wrinkled (shriveled). 5-Sharp line of demarcation between healthy and gangrenous tissue (appear red or bluish zone).
Microscopic Picture: 1-The tissue architecture and cellular details are lost. 2-The intercellular fluid is little and the muscle fibers are closely adhered. 3-Line of defense (b.vs. + neutrophils). 4-Stainability is lost.
2-Moist Gangrene Macroscopic appearance: 1-The affected part is black-greenish, swollen, edematous and soft. 2-The affected tissue is cold and insensitive to touch or pain. 3-Fetid or bad odor. 4-No line of demarcation between the living and gangrenous tissue.
Microscopic appearance: 1-The tissue architecture and cellular details are lost. 2-The intercellular fluid is increased and the muscle fibers are widely separated from each other. 3-Large rode-shaped bacilli on gangrenous tissue.
3-Gas Gangrene It is similar to moist type with presence of numerous gas-bubbles (empty spaces). It gives crepitation on the gross picture. It is caused by gas-forming clostridium.
Sequelae and significance of gangrene 1-Sloughing of tissue (in dry). 2-If small area, absorbed. 3-Toxemia and death (in moist). Table showing the difference between moist and dry gangrene Criterion Occurrence Pathogenesis Macro Putrefaction Line of demarcation Bacterial growth The intercellular fluid
Dry gangrene External tissue Secondary due to ischemia (Arterial occlusion) Dry, shrunken and black Slow Present Slow growth So little (evaporation)
25
Moist gangrene Internal tissue Primary and secondary (Venous and less arterial) Soft, swollen, moist and black Rapid Absent Rapid growth Abundant (no evaporation)
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Temperature Blood supply Spread Toxemia Significance
Wormer Poor No or slow No or mild Toxemia and death
Cold Rich Rapid spread to healthy tissue Severe Sloughing and heel
Postmortem changes It is the chemical and physical changes in the body after death. Aim of these changes is to get rid of these carcasses and change the organic constituents of the carcasses into the original constituents.
Factors affecting these changes: 1-Temperature: high temperature accelerates these changes; but cooling delays it. 2-State of insulation: it depends on i-Skin thickness ii-Sin covering (wool, hair or fur). 3-Animal Species: PM changes in pigs occur very rapidly due to its muscles are moist, soft greasy (rapid putrefaction). While they occur slowly in horse due to dryness and non-greasy muscles. Postmortem changes: They include the following: 1-Rigor mortis 2-Algor Mortis 3-Livor Mortis i-Pseudomelanosis ii-Blood imbibition iii-Bile imbibition 4-Changes in Blood i-PM clotting ii-Blood hemolysis iii-Hypostatic congestion 5-Physical Changes i-PM emphysema ii-PM Tympany iii-Intestinal displacement 6-Chemical Changes i-PM autolysis ii-PM heterolysis
1-Rigor Mortis: It is the stiffness of the carcass after death as a result of contraction of the whole body muscles due to coagulation of myosin. This starts with eyelids, heart (empty left ventricle), diaphragm, thorax, jaws, neck and finally extremities. Its onset within 1-8 hrs after death and continue for 20-50 hrs. The onset of rigor mortis depends on: 1-Cause of death rapid with tetanus or strychnine poison. 2-Health state before death develops early in emaciated animals. 3-Season of death rapidly in summer. NB: If the left ventricle of heart contains blood clots after death, this indicates that either rigor mortis did not occur or a weak myocardium (myocardial degeneration). 26
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
2-Algor Mortis: It is post mortem changes in body temperature. 3-Livor Mortis: It is PM changes in color of tissue. It includes: A-Pseudomelanosis: It is black or greenish pigmentation of the tissue. B-Blood Imbibition: It is pinkish coloration of tissue (Intema of large b.vs. and endocardium) due to hemolysis and diffusion of hemoglobin in tissue. C-Bile Imbibition: Yellowish or greenish coloration of the liver due to bile
4-Changes In Blood: i-Blood Coagulation (Clotting): PM clots may be 1-Currant-jelly Clot (red): It consists of all blood constituents and usually occurs due to rapid death and occupies the lower part of b.vs. and heart. 2-Chicken-fat clot (yellow): It consists of plasma (no RBCs), usually occurs due to slow death and occupies the upper part of b.vs. NB: These clots not attached to the wall of b.vs. Criterion Thrombus PM clot Consistency Dry Moist Features Granular and rough surface Smooth and glistening surface Types Red, White or Mixed Current jelly and chicken fat Attachment to b.vs. Firmly attached to b.vs. wall Not attached Damage of intema Rough intema (damaged) Smooth undamaged intema Main constituents Platelets Fibrin Organization May be present Absent Initiation Initiated by damaged intema Initiated by thromboplastin ii-Blood Hemolysis: It is lysis of RBCs in Hb. iii-Hypostatic Congestion: It is gravitation of the blood in the lower parts of the body due to gravity.
5-Physical Changes: i-Postmortem Emphysema: It is the presence of gas bubbles in the parenchymatous organs. ii-Postmortem Tympany: It is the presence of gas in the stomach. iii-Intestinal Displacement: It is due to the postmortem peristaltic movement.
6-Chemical Changes: i-Postmortem Autolysis: It is self-digestion by cellular enzymes that released into the cytoplasm of the cell after death. It depends on the content of autolytic enzymes, so autolysis occurs early in adrenal glands, brain and pancreas. ii-Postmortem Heterolysis: It is the digestion of the cells by enzymes other than those present inside the cells as enzymes come from putrefactive m.o.
27
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Criterion Normal Tissue RBCs Inflammatory cells Organization
Necrosis Dead beside living (Focal) intact erythrocytes present May be seen
Postmortem changes All is dead (diffuse) Hemolysed Absent Absent
Intracellular and Extracellular Deposition and Degeneration INTRACELLULAR ACCUMULATIONS (PARENCHYMAL DEGENERATIONS OR DYSTROPHIES) Intracellular accumulations: They are the accumulation of abnormal amounts of various substances in the cells. These substances divided into three categories: 1-A normal cellular constituent: accumulated in excess, such as water, lipid, protein, and carbohydrates. 2-An abnormal substance: such as mineral, or a product of abnormal metabolism. 3-A pigment or an infectious product: Parenchymal degenerations occur in functional cells such as: cells of a liver, kidneys, a myocardium and are characterized by accumulation in their cytoplasm proteins, fats and carbohydrates. It is accompanied by decrease (reduction) of function of enzymic systems and occurrence of structural changes in cells. The most causes of parenchymal dystrophies are hypoxia, the intoxication, and also enzymopathy which genetically determined diseases at which is observed an inconsistency of enzymic systems in cells. In result enzymopathy there is an accumulation in cells of any products of a metabolism. Such diseases are named as storage diseases.
Degeneration: It is a reversible biochemical, functional and morphological abnormalities in the cells resulting from any injury not severe enough to cause necrosis. It includes the following items:
1-Disturbance of Protein Metabolism: include 1-Acute cell swelling (cloudy swelling, vacuolar and hydropic degenerations) 2-Mucinous degeneration 3-Mucoid degeneration 4-Amyloid infiltration 5-Hyaline degeneration 6-Gout. II-Disturbance in Fat Metabolism: include 1-Fatty Change (Lipidosis). 2-Obesity (lipomatosis). 3-Lipoidal degeneration. III-Disturbance in Carbohydrate Metabolism: include glycogen infiltration. 28
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
I-Disturbance of Protein Metabolism Acute Cell Swelling Cloudy Swelling, Vacuolar and Hydropic degenerations It is the mildest, reversible retrogressive change of parenchymatous organs and characterized by accumulation of water inside the cytoplasm. Causes: mild irritants as toxin and hypoxia. 1-Toxins: It either i-exogenous toxin: as bacterial, chemical poisons and snake venom or ii-endogenous toxin: as acetone, urea and uric acid. 2-Hypoxia: As in case of respiratory diseases, anemia, and cardiac disease. 3-Fever: 4-Trauma 5-Mild irritant.
Pathogenesis: The energy derived from ATP control the Na-K ion pump within the cell membrane to continuously drive sodium out of the cell exchanging for potassium enter the cell. While in cell injury and damage the mitochondria, the ATP decreased with disturbance in ionic concentration leading entrance of sodium, calcium and water to the cells and the potassium is get out. Accumulation of sodium and water make the cells swollen.
Macroscopic Picture: 1-The affected organ is swollen. 2-Color is pale (bloodless) or parboiled in appearance. 3-Border is round. 4-Cutsection is bulged and appeared convex. 5-The capsule is tense.
Microscopic Picture: 1-The cells are swollen toward the lumen due to the basement membrane prevent the expansion to out side. 2-The lumen is narrowed (star-shape) or obliterated. 3-The peritubular capillaries are compressed by swollen cells so it appears empty (bloodless). 4-The nucleus is not affected. 5-The cytoplasm show fine eosinophilic granules (overshadow the cell boundaries) In cloudy swelling. -or small tiny pale eosinophilic vacuoles around the nucleus In Vacuolar degeneration. These vacuoles have indefinite borders and negative for fat and glycogen staining. -or contains eosinophilic reticulated threads. Some cells burst and may form vesicles In hydropic degeneration
Sequelae or Significance: It is reversible, so if the causes are removed recovery occur. 29
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Mucoid degeneration (Myxomatous degeneration or serous atrophy of fat) It is reversible retrogressive changes of connective tissue and adipose tissue characterized by abnormal accumulation of bluish translucent material (glycoprotein similar to mucin), which is secreted by modified fibroblasts. In serous atrophy of fat the background is pinkish due to the presence of potassium soap. NB: Connective tissue mucin is one of the intercellular components of connective tissue matrix, which is abundant in embryo connective tissue.
Occurrence: 1-Wharton’s jelly. 2-Joint cavity. 3-In adipose tissue in between skeletal muscles, abdominal and coronary fat.
Causes: 1-Malnutrion as in case of cachectic diseases as parasitism and chronic wasting diseases besides starvation. 2-Connective tissue neoplasms as myxoma and myxosarcoma. 3-Myxoedema (a disease associated with thyroid deficiency).
Macroscopic Picture: 1-Size of the affected organs is shrunken. 2-Consistency is flabby. 3-Appearance of the organ is translucent jelly like. 4-Cut surface is watery slimy and stringy material exudes.
Microscopic Picture: 1-The cells are round, oval, spindle and stellate (similar to embryonic cells) with long cytoplasmic processes interlacing with each other (criss-cross). 2-These cells are widely separated by homogenous pale basophilic substance (glycoprotein or mucin-like). 3-The nucleus has the shape of the cells (round, oval, spindle, stellate) and hyperchromatic.
Significance: 1-Mucoid degeneration is very important indicators for general health and nutrition of animals. Mucoid degeneration is reversible. 2-Presence of mucoid degeneration in the neoplasm is indicating of malignancy and the cells become may be quite embryonal. NB: Pseudomucin is normally secreted from the ovarian tissue and paraovarian cyst.
Mucinous Degeneration Mucous Degeneration It is retrogressive changes of the epithelial cells of m.m. characterized by abnormal accumulation of mucin inside the cytoplasm of the epithelial cells. Causes: (similar to catarrhal inflammation) 1-Chemicals: as formaldehyde inhalation. 30
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
2-Inhaled dusts, cold air or foreign protein. 3-Infections as in case of some bacteria and virus. 4-Ingestion of spoiled, moldy or irritating foods.
Macroscopic Picture: 1-It affects the epithelium (m.m.). 2-The mucous membrane is covered with whitish-yellow mucus. 3-Later on the mucus become mucopurulent (invaded by pyogenic). 4-The m.m. may be hyperemic.
Microscopic Picture: 1-The lining epithelium transformed into goblet cells which become filled with mucus. The nucleus pushed toward the basement membrane. 2-These cells may be ruptured into the lumen or desquamated. 2-The mucus is stained bluish (with HE), pink (with PAS) and red (with mucicarmine).
Significance: If the cause is removed, regeneration of the lining epithelium occurs.
Hyaline Degeneration Hyalinosis (hyalos=glass) It is a retrogressive change of tissue characterized by the transformation of the tissue into homogenous structureless translucent smooth material and stained more eosinophilic.
Causes: I-Physiologically:
Hyaline degeneration is present in i-The superficial layer of the skin. ii-Cornea of the eye iii-Ovulation scars of the ovary. II-Pathologically: the hyaline degeneration is due to i-Vit A deficiency (hyperkeratosis) ii-Vit E and selenium deficiencies (Zenker’s degeneration). iii-Chronic glomerulonephritis (hyaline droplet degeneration). iv-Diabetes mellitus (hyaline degeneration in islet of Langerhans cells. v-Alcoholism (Mallory bodies).
Macroscopic Picture: 1-If the hyaline material is small and it is undetectable. 2-In large quantities, the hyalinized tissue is translucent, firm, glassy and shiny. 3-In muscles, they appear grayish-white (fish-flesh) and friable and flabby.
Microscopic Picture: 1-The normal structure of the tissue is transformed into homogenous, structureless and more eosinophilic substance. 2-The nucleus not affected. 3-The hyaline material is stained blue by Gomory trichrome stain. 31
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Types of Hyaline Degeneration: 1-Connective tissue hyaline degeneration. 2-Muscular hyaline degeneration (Zenker’s degeneration). 3-Cellular or epithelial hyaline degeneration.
Connective tissue hyalinosis: 1-The collagen fibers become swollen, fuse together and lose their striations then converted into homogenous structureless and more eosinophilic substances. Examples: i-Old scar and keloids. ii-Mesodermal tumors. iii-Arteriosclerosis. iv-Scleroderma.
Muscular hyalinosis: 1-The muscle fibers are swollen, lose of the longitudinal and cross striations. 2-Lose of Cohenheim field. 3-These fibers appear homogenous structureless and more eosinophilic substances. 4-There is not inflammatory cells. 5-The nucleus not affected. NB: Zenker’s necrosis show pyknotic or absent nuclei and inflammatory cells.
Cellular or epithelial hyalinosis: as 1-Old thrombi: 2-Mallory bodies: hyaline globules inside the cytoplasm of degenerated liver cells of alcoholic drinkers. 3-Corpora amylacea: It is seen in the acini of the mammary gland, lung alveoli and prostate glands. It appears as round, homogenous, or concentrically laminated pink bodies with basophilic tint. 4-Russel’s bodies: They are seen in plasma cells in chronic inflammation. 5-Islets of Langerhans: Its cells undergo hyalinosis in diabetes mellitus. 6-Hyaline casts: These casts are seen inside renal tubules in chronic glomerulonephritis. 7-Hyaline droplet degeneration: It seen in the cells of highly functional renal tubules in case of chronic glomerulonephritis (nephrotic syndrome). Where there is excessive protein filtration from damaged glomeruli and then the tubular reabsorption is overloaded inside the cytoplasm of these cells hyalinosis.
Microscopic Picture: 1-Large eosinophilic refractile droplets in the cytoplasm (overshadow the cell boundaries). 2-The lumen is wide. 3-The nucleus not affected.
Significance: 1-Hyaline degeneration is irreversible condition. 32
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
2-The affected tissue may be calcified (dystrophic). 3-It may lead to rupture of the affected blood vessels and hemorrhage. 4-Hyaline casts in kidney indicates albumen-urea.
Amyloid Infiltration Amyloidosis It is retrogressive changes characterized by abnormal extracellular deposition of substance resembling the starch (amylum) in its chemical reaction. This substance is pale eosinophilic homogenous structureless substance deposited in loose connective tissue sub endothelial cells of blood vessels. Ultrastructurally, the amyloid consists principally of fibrilar protein and small separate components of glycoprotein.
Mechanisms of amyloid deposition: The essential element in amyloid deposition is the production of a protein which is either amyloidogenic itself or modified to become amyloidogenic.
Amyloid Proteins: 1-Amyloid-A Protein (AA): This protein is closely related to acute phase reactive protein which appears in the serum in many inflammatory conditions. 2-Amyloid Light Chain Derived Protein (AL): This protein is derived from fragments of immunoglobulin molecules (particularly Lambda light chains) and is essentially a product of plasma cells. The important fact about these proteins is that they form specific fibrils in which the molecules of constituent polypeptides are arranged in a most unusual fashion called β-pleating which imparts to amyloid its specific chemical staining characteristics and accounts for its resistance to degeneration.
Mechanism of amyloid deposition diagram: Long standing active inflammation
Abnormal proliferation of plasma cells
Acute phase reactant protein Abnormal Igs (Lambda light chains) Proteolysis (with macrophages) Proteolysis Amyloidogenic Protein (AA) Amyloidogenic Protein (AL) β-pleating Amyloid (AA) Amyloid (AL) NB: Amyloidogenic protein and polypeptides may also occur in other conditions as tumors of endocrine glands producing polypeptide hormones (calcitonin, insulin). In old age: minor deposits of amyloid may occur in the heart and brain (the amyloidogenic protein is related to prealbumin). 33
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Classification of amyloidosis: I- Generalized or Systemic Amyloidosis: It either derived from: i-Abnormal (monoclonal) proliferation of plasma cells (AL) as in myelomatosis. ii-Acute reactant protein (AA) as in TB, Osteomyelitis, Hodgkin’s disease. II-Localized Amyloidosis: It is derived from endocrine polypeptides and prealbumin. Types of Amyloidosis: I-Primary amyloidosis (immunocyte dyscrasia: defect in blood). II-Secondary amyloidosis (reactive systemic amyloidosis). I-Primary amyloidosis (immunocyte dyscrasia): 1-It occur rarely and with unknown causes. 2-It seen in two forms i-Localized form (in single organ). ii-Generalized or systemic form. 3-It is seen in the heart, tongue, intestine, skin and skeletal muscles. II-Secondary amyloidosis (reactive systemic amyloidosis): The secondary type occurs as a complicated of long-standing destructive diseases as: i-Chronic suppurative conditions: as chronic suppurative arthritis, chronic suppurative osteomyelitis, lung abscess, chronic pyelonephritis and empyema (pus in a cavity). ii-Chronic granulomatous diseases: as tuberculosis and leprosy. iii-Malignant tumors: as multiple myeloma and renal carcinoma. iv-In horse, during production of antitetanic serum.
Staining of amyloid substance: I-Clinically detection of amyloid (during life) by using congo-red stain: Injected dye in one leg and collected blood from another leg and then examined the serum for the stain by spectrophotometer. i-Less than 50% of the dye disappeared no amyloidosis occur. ii-6o% or more of the dye disappeared amyloidosis present. II-Detection of amyloid in organs (PM): 1-Lugol’s iodine in case of amyloid give mahogany brown (normal blue). 2-Iodine with 1%sulphuric acid gives blue. III-Detection of amyloid in paraffin sections: 1-HE Pink in color. 2-Methyl violet 3-Crystal violet Rose red in color. 4-Gention violet 5-Congo red Orange red in color. 6-Picro-fuchsiun Yellowish-brown in color.
Pathogenesis: The amyloid substance (pale eosinophilic structureless) deposited in the loose c.t. of subendothelial cells of blood vessels. This substance affects 34
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
i-On the adjacent tissue of affected organ
ii-On the blood vessels inducing either
inducing
-Pressure atrophy -Disarrangement or -Gradually replaced by The amyloid substances
1-Narrowing of the lumen
2-Thickening the wall of b.vs. with -Increase permeability
Transudation (edema) -Lack of blood supply Atrophy -Hypoxia or anoxia retrogressive change (fatty change) and necrosis.
Macroscopic Picture: 1-Size: enlarged and heavy. 2-Consistency: firm. 3-Borders: sharp. 4-Color: pale. 5-Cut surface: flat waxy translucent surface (glistening). NB: Amyloid is most prominent in spleen, liver and kidneys.
Amyloidosis in Liver Macroscopic Picture: 1-Size of liver is enlarged and heavy. 2-Borders: sharp. 3-Color: light brown streaks among yellowish streaks (fatty change). 4-Consistency: firm. 5-Cut surface: smooth waxy translucent surface.
Microscopic Picture: 1-Pale eosinophilic homogenous substance deposited in the loose connective tissue subendothelial cells of hepatic arterioles, venules and sinusoids. 2-These arterioles, venules and sinusoids are narrowed or obliterated. 3-The hepatic cells suffered pressure atrophy and disarrangement of its hepatic cords. 4-Fatty changes and necrosis may be seen in the hepatic cells. 5-In the advance cases, the liver cells gradually replaced by the amyloid substance. 35
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Significance: 1-The amyloidosis is irreversible. 2-It leads to hepatic failure. 3-It leads to rupture of the liver, hemorrhage and death.
Amyloidosis in the Kidney Macroscopic Picture: 1-The kidney become enlarged and heavy in early stage and become contracted (small) in late stage due to ischemia. 2-Cut surface: waxy light brown dots (amyloid in the glomeruli) among pale yellow streaks (fatty change).
Microscopic Picture: 1-Pale eosinophilic homogenous substance is deposited firstly in the media of the afferent arterioles, then the subendothelial cells of glomeruli and intertubular capillaries under the basement membrane. 2-The renal tubules become atrophied and show fatty change and fibrosis (contracted kidney).
Significance: 1-The amyloidosis in the kidney is irreversible. 2-It leads to uremia, hypertension, general edema and diabetes insipidus.
Amyloidosis in the Spleen There are two types according the distribution of the amyloid into: I-Focal Amyloidosis (Sago spleen). II-Diffuse Amyloidosis (Bacon spleen).
I-Focal Amyloidosis (Sago spleen): Macroscopic Picture: 1-The spleen is moderately enlarged. 2-Consistency is rubbery and firm. 3-Cut surface show waxy light brown dots against red background (resemble the sago grain) Sago spleen.
Microscopic Picture: -The amyloid substance is deposited in the wall of central arterioles and gradually replaced the white pulp only.
II-Diffuse Amyloidosis (Bacon spleen): Macroscopic Picture: 1-The spleen is enlarged than the focal type. 2-Lardicaeous in consistency as if it infiltrated with melted lard. 3-Cut surface show diffuse waxy translucent light brown streaks. 36
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Microscopic Picture: -The amyloid substance is deposited in both white and red pulp (around central arterioles and splenic sinusoids then replaced their structures).
Significance: 1-It leads to immune deficient patient. 2-Hemorrhage and death.
Gout It is a retrogressive changes characterized by deposition of uric acid and urates (Na and Ca urates) in joints (articular gout) and visceral organ (visceral gout in birds). NB: Uric acid and urates is the end product of purine metabolism.
Causes: 1-Heriditery cause in middle-aged male. 2-High protein diet (containing nuclei as liver and kidney). 3-Disturbance in the renal function (Nephrogenic strain of IB virus). 4-Vit A deficiency. 5-Insuffient exercise.
Pathogenesis: Gout is not seen in domesticated animals due to presence of uricase enzymes in their liver, which convert uric acid to allantoins, which excreted in urine. In birds, the uric acid and urates start to deposit in the kidneys and on the serous membrane of internal organs when the level of them are elevated. In man, articular form only observed. In the dogs convert the 1/3 of uric acid into allantoins and excreted in the urine. NB: The normal serum level of uric acid = 3-4 mg/dl and if reach to 6-12 mg/dl deposited in the tissue.
Types of Gout: I-Articular gout: deposited on the articular surface of joints. II-Visceral gout: deposited in kidneys and serous membrane.
I-Articular Gout: Macroscopic Picture: 1-The joints are enlarged (swollen), deformed and immobile (loss function). 2-The joint surface and surrounding fibrous tissue are covered by chalky-white material (tophi). 3-If the tophi are present in the subcutaneous tissue, ulceration and discharging chalky material outside. NB: Tophi are concentration of gouty material on the articular surfaces. 37
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Microscopic Picture: 1-Eosinophilic needle-like crystals or irregular round unstained crystals of urates on the articular surfaces and surrounding tissue. 2-Inflammatory cells are not present or rare (neutrophils, macrophages and giant cells).
II-Visceral gout: Macroscopic Picture: 1- Thin layer of chalky-white material covers the serous surface of pericardium, liver and peritoneum. 2-The ureters are impacted or filled with chalky-white material.
Microscopic Picture: 1-Radiating eosinophilic (Ca urates) and basophilic (Na urates) in the renal tubules and on serous membrane. 2-Pressure atrophy of adjacent renal tubules. 3-Granulomatous reactions are seen (neutrophils, macrophages, foreign body giant cells and fibroblasts). 4- Degenerative changes, necrosis and fibrosis also occur.
Significance: 1-The gout is an indicator of disturbance in protein metabolism. 2-The articular gout in human is badly recurrent. 3-Visceral gout in birds is serious disease causing deaths.
II-Disturbances in Carbohydrate Metabolism Glycogen Infiltration It is excessive abnormal intracellular accumulation of glycogen in tissue particularly in the liver, kidneys and pancreas.
Causes: 1- Diabetes mellitus and uncontrolled hyperglycemia. 2-Glycogen storage diseases in infants (Von Gierke’s disease) resulted from congenital absence of glucose 6- phosphatase which is necessary for the breakdown of glycogen into glucose. 3-Renal carcinoma and seminoma.
Macroscopic Picture: 1-It is not detected grossly in small amount. 2-While if large amount glycogen is infiltrated, the affected organs is very enlarged and whitish or anemic in appearance. 38
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
NB: -For glycogen demonstration, the tissue must be fixed immediately after death in the Carnoy’s fluid or absolute alcohol.
Microscopic Picture: In Liver: 1-The hepatic cells are swollen. 2-Foamy granular cytoplasm (contains irregular and hazy vacuoles). 3-In severe condition, the nucleus is affected (enlarged and empty with clear nuclear membrane).
In Kidneys: 1-The renal epithelium are swollen. 2-The cytoplasm is vacuolated. 3-No nuclear changes.
Significance: -The glycogen infiltration is of minor important. NB: The special stains of glycogen are Best’s carmine stained it crimson red by and PAS stained it red.
III-Disturbances in Fat Metabolism 1-Fatty Change (Lipidosis). 3-Lipoidal degeneration.
2-Obesity (lipomatosis).
1-Fatty Change (Lipidosis) It is a retrogressive changes characterized by abnormal intracellular accumulation of neutral fat (triglycerides) in non-fatty tissue, particularly in the parenchymatous organs (liver, kidneys and heart). NB: The body fats occur in 3 forms: i-Un-masked (Visible) fat: as neutral fat (storage in fatty depots). ii-Masked (Un-visible) fat: It is combination with the protoplasm (not stained by fat stains) as phospholipids. iii-Lipoidal substance: That are fat-solvents (sometimes stain with dyes). They include cholesterol other constituents of myelin, adrenal cortex and CL.
Causes: Any agents interfere with the fat metabolism. 1-Toxins: interfere with synthesis of phospholipids i-Bacterial toxins: diphtheria, TB, ii-Chemical toxins: as alcohol, carbon tetrachloride, benzol. 2-Hypoxia or Anoxia: lack of oxygen lack of energy synthesis of phospholipids as in case of 39
interfere with
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
i-Severe anemia ii-Chronic venous congestion, iii-Cardiac failure and iv-Respiratory disease. 3-Deficiency of lipotropic factors: (choline, methionine, cystine, cysteine). i-Deficiency of leads to decrease phospholipids synthesis. ii-Absence of these lipotropic factors leads to esterification of diglycerides into triglycerides. iii-helps in the formation of neutral fat, fatty changes and obesity. 4-Failure of protein synthesis: to form lipoproteins. 5-Diatery causes: i-Excessive intake of fats and carbohydrates. ii-Starvation with mobilization of fats from fat-depots. 6-Diseases of the liver cells: as viral hepatitis lead to fatty change.
Fatty Changes in the Liver The fatty change in the liver are either: 1-Diffuse: in case of severe anemia and toxemia. 2-Patchy (focal): Centrilobular in CVC. Peripherolobular in mild toxins.
Macroscopic Picture: 1-Size: enlarge and float on the surface of water in advanced stage 2-Color: yellow 3-Consistency: soft or flabby with tense capsule. 4-Borders: round. 5-Cut surface: bulge and greasy with fat-globules on the knife.
Microscopic Picture: 1-The hepatic cells are swollen.
2-In Early Stage: i-The cytoplasm of affected cells contains minute fat globules (vacuoles) around the nucleus. ii-The nucleus not affected and centrally located.
3-In Lat Stage: i-The minute globules of fat fuse together forming large globule (vacuole), which pushes and flattened the nucleus to periphery the cell “the signet-ring appearance�. ii-Some liver cells are ruptured on each other to form mass of fat (fatty cysts).
4-Special stain of fat: the fat appears as rounded sharp vacuoles with HE 40
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Special stains of fat Sudan III Sudan IV (Scarlet red) Oil red O Osmic acid Sudan black B Nile blue sulfate
Stained the fat (frozen sections) Yellow Orange Red Black Black Fatty acid: bluish Neutral fat reddish
Fatty Changes in the Heart Macroscopic Picture: -The heart is 1-Size: enlarged and with round apex. 2-Consistency: soft or flabby and friable with dilated chambers. 3-Color: pale yellow (in diffuse) or yellow streaks alternating with brown ones giving the heart “Tabby-cat or Tigeroid appearance” or yellow spots alternating with brown spots giving the heart “Thrush-breast striation”.
Microscopic Picture: 1-Minute fat globules (vacuoles) are arranged in longitudinal rows in cardiac muscles. 2-Absence of cross striations. 3-The nucleus is not affected
Fatty Changes in the Kidneys 1-The fat globules are deposited in the cells of proximal and distal convoluted tubules besides ascending loop of Henle. 2-These globules are deposited between the nucleus and the basement membrane.
Significance: 1-Necrosis and cirrhosis of the liver. 2-Acute heart failure. 3-Fat emboli (open on blood capillaries).
2-Obesity (Lipomatosis) It is excessive accumulation of fat in fat-depots (S/C, omentum and mesentery, perirenal and pericardium).
Causes: 1-Excessive fat and carbohydrates intake. 2-Low metabolic rate. 41
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Microscopic Picture: The muscle fibers appeared normally or suffered pressure atrophy.
Significance: -It interferes with function of organs as heart, lungs and diaphragm. -Rapid respiration and pulse rate (fatigue). -May cause rupture of internal organs as liver. NB: Steatosis is the replacement of a tissue (liver and muscles) with fat.
3-Lipoidal Degeneration It is the deposition of cholesterol in the tissue especially the intema of the blood vessels leading Atheroma or Arteriosclerosis.
I-Atheroma: It is a disease of primates where the intema is thickened by lipids, cholesterol and fibroblasts. It is usually focal.
Macroscopic Picture: -The lesions appear as raised yellow plaques.
Microscopic Picture: 1-Cholesterol lenticular spaces (cholesterol clefts). 2-Many macrophages with vacuolated or foamy cytoplasm. 3-Fibroblasts and calcification may be seen.
II-Arteriosclerosis: It is the hardening of arteries.
Causes: i-Senility. ii-Wasting diseases as Johne’s disease.
Pathogenesis: -The changes start in the media of aorta and coronaries. -Then extend to the intema and adventitia.
Microscopic Picture: i-Hydropic degeneration of the lining endothelium. ii-Aggregations of foam cells (vacuolated macrophages). iii-Cholesterol clefts. iv-Intense lymphocytic infiltration in adventitia. v-The intemal endothelial cells become proliferated and fibrosed. vi-Dystrophic calcification and cellular debris. NB: The umbilical vessels show calcified media and intema at birth. 42
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Raised yellowish-white plaques which may round or oval (up to 20 mm in diameter) are grossly seen.
List and differentiate between the lesions induced intracellular vacuolation. Criterion 1-The nucleus 2-The vacuoles 3-Special stains
Vacuolar degeneration Not affected Faint pink and ill distinct borders - Ve
Glycogen infiltration Enlarged and empty Irregular and hazy
Fatty Changes Pushed and flattened Sharp and large
Best’s carmine PAS
Sudan III, IV, black B Oil red O, Osmic acid
Calcification It is a pathological deposition of calcium salts in soft tissues rather than osteoid tissue (ossification). The calcium salts are usually in the form of phosphates or carbonates.
The plasma level of calcium is controlled i-Parathyroid hormone: causes hypercalcemia through bone resorption. ii-Calcitonin: causes hypocalcemia. iii-Vitamin D helps in the absorption of calcium from the intestine. NB: Normal blood calcium is 10 mg/dl.
The pathological calcification is divided into: 1- Metastatic (general) calcification. 2- Dystrophic (local) calcification. 3-Calcinosis circumscripta that present in the dermis of the skin of dog and man (1-10 cm in diameter) and white-chalky.
1-Metastatic (General) Calcification This type of calcification follow increased blood calcium level without necrosis or degeneration of tissues. It observed in acid-producing organs as stomach (Hcl), kidneys (phosphatic acid) and lungs (carbonic acid).
Causes: 1-Hyperparathyrodism and excess of Vitamin D. 2-Osteoperosis and osteomalacia. 3-Multiple myeloma and tumors of bones. 4-Renal failure with retention of phosphate.
2-Dystrophic (Local) Calcification It is the deposition of calcium salts in the necrotic or degenerated tissues. Dystrophic calcification has no relation with calcium content of blood (normal). 43
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Pathogenesis: In dystrophic calcification, the calcium needs an alkaline media to deposit in it. This media is present in necrotic and degenerated tissues, where the circulation is deficient and the carbon dioxide tension is low (alkaline media).
Macroscopic Picture: 1-If the deposition become free from the surrounding tissue, the calcium is white or gray granular in appearance. 2-Grating sound and gritty feeling are recorded in cut section.
Microscopic Picture: 1-Bluish irregular fine granular deposits are seen replacing and among the necrotic (dystrophic) or normal (metastatic) tissue when stained by HE. 2-Special stains of calcium: i-Von Kossa’s stain stained the calcium black. ii-Alizarin-red-S technique stained the calcium red.
Significance: Calcification is usually permanent and harmless.
IV-Disturbance in Pigment Metabolism Pigments: They are colored substances, which are present intra or extracellular. Pigmentation: Deposition of pigments in the tissues. Types of Pigmentations: I-Endogenous Pigmentation II-Exogenous Pigmentation (Formed inside the body (Formed outside the body) Enter the body either: i-Hemoglobin pigment A) By Inhalation (pneumoconiosis) -Hemosiderin - Anthracosis - Siderosis -Hemotoidin - Silicosis - Chalicosis -Porphyrins - Asbestosis - Baritosis a-Osteohemochromatosis - Kaolinosis - Stannosis b-Photosensitization B) By Ingestion ii -Melanin - Argyrosis - Plumbism iii-Lipofuscin - Lipochromatosis - Xanthomatosis iv -Ceroid Pigments C) Through the skin e.g. tattooing.
I-Exogenous Pigmentations A) By Inhalation: Pneumoconiosis: It is accumulation of the mineral dusts in the lungs and the tissue reactions to its presence. 44
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Pathogenesis: When the dusts (insoluble) inhaled, these pigments are trapped by mucus covering the lining epithelial of bronchi and bronchioles, other pigments are settled down on the epithelium of air sacs the phagocytized by macrophages (dust cells) travel to regional lymph nodes or accumulated around bronchioles and in the interalveolar connective tissue septa Fibrosis of the lungs with granulomatous reactions (macrophages and giant cells). Effects of Pneumoconiosis: 1-No effects or minimal fibrosis as in case of anthracosis. 2-Focal fibrosis as in case of silicosis, kaolinosis and siderosis. 3- Diffuse fibrosis as in case of asbestosis.
Fate or Sequelae of Pneumoconiosis: 1-Bronchiolectasia: Dilation of bronchioles due to collagen formation (fibrosis) around the bronchioles maturation and shrinkage pull the wall of bronchioles dilation of the lumen. 2-Compensatory emphysema: Over inflation of the air sacs with air due to obliteration of some air sacs by fibrosis. 3-Predisposing factors to infection especially with tuberculosis due to lowering in the resistance. 4-Adhesion between the visceral and parietal pleura difficult breathing and hypoxia. 5-Core Pulmonal: hypertrophy of the right side of the heart, due to back pressure. 6-Death occurs due to heart failure and anoxia.
Anthracosis Black-lung Disease Definition: It is pneumoconiosis from inhaling coal-dust (carbon particles). Causes: Inhalation of coal dusts for long period, smoking and in animals and peoples work in the mines or live in big towns. Macroscopic Picture: 1-Large grayish to black spots on the surface of the affected lungs. 2-The ventral portions are affected more than the dorsal ones. 3-The lymph nodes are brown to black, particularly at the medulla. The color is normally seen in the bovine lymph nodes; but it is due to recently hemolysed blood (not seen microscopically).
Microscopic Picture: 45
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
1-Minute black granules (carbon particles) are seen free or inside the dust cells either on the epithelial lining of bronchioles, and air sacs and interalveolar connective tissue septa. 2-This pigment is observed in the regional lymph nodes. 3- Fibrosis occurs when contaminated with silica. Significance: Coal dusts are permanent and harmless.
Silicosis Definition: It is pneumoconiosis from inhaling fine silica particles (silicon dioxide). Causes: Inhalation of silicon dioxide for long period.
Pathogenesis: Most of the silica dusts are trapped by nasal barrier. Some fine particles are escaped to the bronchioles (terminal bronchioles) and air sacs then phagocytized by alveolar macrophages (dust cells) travel through lymphatics to regional lymph nodes then to outside. Some of these macrophages containing pigments are settled in the lung tissue and die secrete chemical mediators to enhance the inflammatory process and stimulate fibrous connective tissue proliferation. This reaction occludes the lumens of bronchioles (forming silicotic nodules).
Macroscopic Picture: 1-The lungs are nodular and firm. 2-They have no color except if it is contaminated with coal dust (black).
Microscopic Picture: 1-The silicotic nodules are represented by i-Central terminal bronchiole containing silica particles (seen with polarized light). ii-Surrounded by macrophages, giant cells and fibroblasts. 2-Coalescence of nodules together and press on the blood vessels lymphatics, bronchioles and obliterate the alveoli. 3-Focal areas of compensatory emphysema. 4-Later, these nodules became a cellular and hyaline (forming pulmonary corpora amylacea). Significance: as pneumoconiosis.
Asbestosis Definition: It is pneumoconiosis from inhaling asbestos fibers (magnesium silicate). Causes: Inhalation of asbestos fibers for long period.
46
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Pathogenesis: When the asbestos fibers (more than 20 um) enter the pulmonary tissue, chronic inflammatory reactions are developed around these fibers. Some of these fibers destructed (sequestration) and other lodge in respiratory bronchioles and air sacs and then become coated by protein containing iron forming “ferruginous bodies� that appear as bamboo-like sticks (brownish in color).
Macroscopic Picture: 1-The lungs are grayish and firm. 2-The pleura are thickened.
Microscopic Picture: 1-Diffuse pulmonary fibrosis. 2-Brown bamboo-like sticks (long, segmented and with rounded ends). 3-Chronic inflammatory reactions around the asbestos fibers. Significance: similar to pneumoconiosis.
Kaolinosis Definition: It is pneumoconiosis from inhaling particles of kaolin (China clay). Causes: Inhalation of China clay for long period.
Macroscopic Picture: -The lungs are grayish in color, firm and nodular.
Microscopic Picture: 1-These nodules represented by homogenous faint basophilic material (kaolin) surrounded by fibrous connective tissue (focal fibrosis). 2-Sometimes, the kaolin particles are seen inside the macrophages as anisotropic crystals. 3-Granulomatous reactions (macrophages and giant cells).
Siderosis Definition: It is pneumoconiosis from inhaling the iron oxide (rust).
Macroscopic Picture: 1-The lung tissues are brownish in color. 2-Firm in consistency. 3-The organ becomes blue when immersed in Prussian blue stain.
Microscopic Picture: 1-Brownish granules inside the macrophages. 2-Fibrous connective tissue proliferation (focal fibrosis). 3-These pigment is stained blue by Prussian blue stain. 47
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
N.B: Baritosis: It is pneumoconiosis from inhaling barium oxide. Stannosis: It is pneumoconiosis from inhaling tin oxide. Chalicosis: It is pneumoconiosis from inhaling calcium carbonate (chalk).
B) By Ingestion: Argyrosis: It is the deposition of silver salts in the skin, conjunctiva and internal organs due to prolonged medication of silver drugs. Plumbism: It is the pigmentation of tissue resulting from ingestion of small amount of lead salts that produce black or blue line on the gum adjacent teeth (Abortous line or lead line) due to reaction of lead salts with H2S Lead sulphid (black or blue in color). N.B: The H2S is liberated by putrefactive bacteria. Steatitis of mink, kits and pigs: It is the inflammation and pigmentation of fat in mink, kits and pigs due to Vit. E deficiency and it is characterized by formation of Yellow acid-fast pigments (Ceroid pigments) inside the inflamed fat cells and macrophages.
Xanthomatosis It is orange to yellow pigmentation of wattle and skin of White Leghorn pullets. Causes: Ingestion of excessive amounts of carotene and xanthophylls. Macroscopic Picture: -The affected areas of the skin is thickened (tumor like masses) and orange to yellow color. Microscopic Picture: 1-These masses consist of foam cells, fibroblasts, lipid droplets and cholesterol clefts (lenticular spaces). 2-Orange to yellow pigments are seen in epidermis, dermis and subcutis of wattles. Exogenous hemochromatosis: It is exogenous pigmentation with hemosiderin in man caused by repeated blood transfusion (hemolysis of RBCs.).
Lipochromatosis Brown Atrophy of Heart or Muscles Definition: It is the deep yellow, orange and brown pigmentation of atrophied organs or tissue due to black pigments related to Lipofuscin (20% fat, 14% nitrogen, and 0.4% phosphors beside yellow pigments). Occurrences: (intracellular): -Lingual, masseter and cardiac muscles. 48
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
-Diaphragmatic, cervical and leg muscles. -Thoracic and abdominal muscles. -Liver, adrenals, thyroid, parathyroid, lymph nodes and ovaries.
Causes: -Senility. -Cachexia (severe malnutrition and chronic wasting diseases).
Macroscopic Picture: -The affected muscles or organs are dark brown and atrophied.
Microscopic Picture: 1-Yellow to brown granules of Lipofuscin appears at the poles of the nuclei as in cardiac muscles, around the nuclei in the liver cells or in any part in skeletal muscles. 2-These granules are stained with fat stains and are not soluble in fat solvents (not true fat).
Significance: -It is harmless. -Its presence points some wasting diseases or senility.
C) Through the skin: Tattooing: The pigments (tattooing ink) introduced through the skin to the dermis and subcutis of animal to identify them. 1-The pigment is phagocytized by fixed macrophages, and then keeps them permanently. 2-Some pigments may be seen in the regional lymph nodes without inflammatory reactions.
II- Endogenous pigmentations Hemoglobin-Derived Pigments 1-Hemoglobin. 2-Hemosiderosis. 3-Hemotoidin. 4-Jaundice.
Hemoglobin pigmentation The hemoglobin pigments may be seen in the vicinity of a large hemorrhage in avascular tissue as cartilage. N.B:
49
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Excessive hemolysis of RBCs. Hemoglobin (increase in plasma, which is red in color) Heme + Globins (used in formation of new RBCs) Hemotoidin (porphyrin) + iron (hemosiderin) used in formation of new RBCs . Biliverdin Reduced to Bilirubin circulate in the blood as free bilirubin + Albumin Unconjugated Bilirubin (prehepatic or hemobilirubin) enter the liver in the liver cells + Glucouronic acid + transferase enzyme Conjugated bilirubin (posthepatic or cholebilirubin) pass with the bile to intestine. Stercobilin Stercobilinogen (Give the color of feces) Absorb to the blood then to the kidneys Urobilin Urobilinogen (Give straw yellow color to urine) Remark: The cholebilirubin and Urobilinogen is passing through the renal filter; the hemobilirubin can not pass.
Hemosiderin pigment (Hemosiderosis) Definition: It is the brownish discoloration of different tissue due to excessive deposition of hemosiderin pigments (iron).
Causes: i-Old hemorrhages ii-Hemolytic anemia iii-Chronic passive hyperemia
Pathogenesis: -The iron-containing pigments (hemosiderin) is liberated from hemolysed RBCs and phagocytized by macrophages (siderocytes) and parenchymatous cells of the liver and kidneys.
Macroscopic Picture: 1-The affected tissues are brownish in color. 2-The lungs are firm and indurated (brown induration of the lung).
Microscopic Picture: 1-Golden yellow amorphous granules are seen inside siderocytes (kupffer cells in the liver and heart failure cells in the lungs). 50
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
2-The hemosiderin is stained blue by Prussian blue stain {potassium ferrocyanide + ferric (iron in hemosiderin) Ferric Ferrocyanide.
Significance: -It’s presence indicates hemolysis of RBCs. or hemorrhages.
Hemotoidin Definition: It is one of the breaks down products of hemoglobin. It is found at the sites of old hemorrhages and stained the tissue yellow. It appears as extracellular, yellow and rhombic crystals, and soluble in tissue fluid. Differences between hemosiderin and hemotoidin Hemosiderin Golden-yellow amorphous granules Iron-containing pigments Intracellular (siderocytes) Insoluble in tissue fluid Stained blue with Prussian blue stain
Hemotoidin Yellow rhombic crystals Iron-free pigments Extracellular Soluble in tissue fluid Negative for Prussian reaction
Jaundice (Icterus) Definition: It is the presence of excessive amount of bilirubin (bile pigment) in the blood and yellow discoloration of tissue especially the mucous membranes and intema of large blood vessels.
Classification of Jaundice: I-According to the cause 1- Hemolytic Jaundice 2-Toxic Jaundice 3- Obstructive Jaundice
II-According to the anatomy 1-Prehepatic Jaundice 2-Intrahepatic Jaundice 3-Posthepatic Jaundice
The bilirubin content in the blood depends upon: i-The rate of erythrocyte destruction. ii-Functional capacity of liver cells. iii-Patency of biliary ducts.
1-Hemolytic (prehepatic) Jaundice Definition: It is an increase of bilirubin (hemobilirubin) in the blood due to excessive hemolysis of RBCs.
Causes: 1-Excessive hemolysis of RBCs. due to bacteria, viral (equine infectious anemia), Parasitic (Babesia) and poisonous materials. 2-Massive internal hemorrhages 3- Neonatal Jaundice due to Rh- Factor. 51
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
Macroscopic Picture: -Yellow coloration of skin, mucous membrane, conjunctiva, sclera of eye and intema of large blood vessels and aorta.
Microscopic Picture: 1-The liver is normal (No necrosis). 2-The bile ducts are patent. 3- Excessive hemolysis of RBCs, which evident by hemosiderosis in different tissue (liver, spleen and lungs). 4- The bile pigment is not seen.
Significance: -The bile pigments are harmless (bile salts is toxic) -It’s presence indicates severe hemolytic condition -The hepatic function is normal.
2-Toxic (Intrahepatic) Jaundice Definition: It is an increase of bilirubin (hemo and cholebilirubin) in the blood due to destruction of the hepatic cells.
Causes: Degeneration and necrosis of hepatic cells are due to bacteria, virus, parasites, fungus and toxins.
Pathogenesis: -The degenerated or necrotic hepatocytes can not convert the normal amount of hemobilirubin (Unconjugated) to cholebilirubin so it is increased in the blood. Moreover, the degeneration and necrosis of the hepatic cells leads to break down of bile canaliculi and open into the blood of hepatic sinusoids to increase of cholebilirubin (conjugated).
Macroscopic Picture: 1-Intense yellow coloration of the affected tissues.
Microscopic Picture: 1-Degeneration and necrosis of hepatic cells. 2- No hemosiderosis. 3-The bile ducts is patent. 4-The bile pigments are not seen.
Significance: -Disturbance in hepatic function
52
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3-Obstructive (Posthepatic) Jaundice Definition: It is an increase in the bilirubin (cholebilirubin) in the blood due to obstruction of bile pathway (bile ducts).
Causes: Obstruction of bile pathway may be due to parasites (Fasciola, Ascaris), gall stones, pressure on bile canaliculi and ducts.
Pathogenesis: -The cholebilirubin, produced by normal hepatic cells, can not pass to intestine due to obstruction to its flow. So its presence and increase in the bile ducts could diffuse the bile to surrounding tissue then to the lymphatics and blood (cholebilirubin).
Macroscopic Picture: 1-Yellowish coloration of the body tissues. 2-The bile ducts are obstructed. 3-The liver tissue is stained yellow by bile. 4-The feces is -Clay in color (Stercobilinogen). -Greasy (Steatorrhea) due to presence of undigested fat.
Microscopic Picture: 1- The bile duct is obstructed. 2- The bile canaliculi are over distended with bile. 3- The bile pigments are seen among the hepatic cells. 4- No hemosiderosis. 5- The liver cells are normal.
Significance: -There is partial or complete obstruction of bile pathway. -Bile pigments are harmless -The liver function is normal.
Van den Bergh Test Definition: It is a test applied to differentiate between different types of bilirubin or jaundice (positive test give pink or purple color, within 2 minutes, with the cholebilirubin.
53
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Diazotized sulfonilic acid Consists of Sodium nitrite Hcl Sulfonilic acid Plasma or serum (Treated with alcohol)
Pink
1-Direct Reaction: -Positive (pink in color within 2 minutes) with cholebilirubin (obstructive jaundice). 2-Indirect Reaction: No color develop except if add few drops of alcohol (indirect positive) with hemobilirubin (hemolytic jaundice) 3-Biphasic Reaction: With toxic jaundice due to presence of hemo and cholebilirubin.
Differences between types of jaundice Criteria Type of bilirubin The liver The bile pathway The bile pigments Hemosiderosis Feces
Hemolytic Jaundice Hemobilirubin Normal Normal Not seen Present in the tissue Normal
Toxic Jaundice Hemo & Chole Necrotic Normal Not seen Not present Normal
Obstructive Jaundice Cholebilirubin Normal Obstructed Are seen among cells Not present Clay and Greasy
Porphyrins Photosensitizing Pigments Photosensitization Photosensitizational Dermatitis Definition: It the development of abnormally heightened reactivity of the skin to sunlight. It occurs in cattle, sheep, goats, pigs and occasionally horses.
It is developed under 3 factors: 1-Photodynamic agents (endogenous or exogenous chemicals) as porphyrins, phenothiazine and sulfonamides. 2-Cutaneous absorption of solar radiations (ultraviolet and visible lights). 3-The period of exposure to sufficient amount of UV-rays.
54
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Classification of Photosensitization: 1-Type-I or Primary photosensitization: In which the photodynamic agents (plant pigments or drugs) are ingested, absorbed and enter the systemic circulation to induce photosensitization. 2-Type-II or Congenital Photosensitization: In which there is an inherited metabolic defects in porphyrin metabolism accumulation of porphyrins in the body to induce photosensitization. 3-Type-III or Secondary or Hepatogenous or Hepatotoxic Type: In which there is interference with the excretion of phylloerythrin (metabolic products of chlorophyll). Thus, this type occurs in the animals feed on green foods, which contain chlorophyll that break down in gut to phylloerythrin pigments (porphyrins). It circulates in the blood and removed by the normal liver and excreted with the bile. In case of diseased or damaged liver or Biliary stasis there is accumulation of phylloerythrin pigments in blood and induces photosensitization.
Pathogenesis: Direct action of sun lights on a photodynamic pigments that absorb the UV lights and energy. This energy either transferred I- Directly to II- Indirectly through The oxygen in the cytosol of the cells The activation of Xanthin oxidase calcium-dependent proteases Leads to formation of Oxygen free radicals Cause Peroxidation of the cell membrane Rupture of the mitochondria and lysosomes Degranulation of the cutaneous mast cells Liberation of chemical mediators (histamine) Severe inflammation (photodermatitis) Atopic Dermatitis
Clinical Signs: 1-Burning or itching sensations. 2-Erythena and pronounced inflammatory edema. 55
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3-Areas of the skin become necrotic or slough.
Lesions: 1- Redness. 3-Water discharge.
2- Vesicle formation. 4-Necrosis of the epidermis.
Osteohemochromatosis (Pink tooth) Definition: It is pigmentation of bone either brown or black in adult; while in young, the dentine becomes red or pink in color (pink tooth). It is due to excessive porphyrin production (formation of pyrrol radicals).
Causes: 1- Congenital porphyria. 2- Toxic hepatic injury 3- Poisoning with lead, copper or zinc.
Melanin Definition: It is sulphur-containing protein that produced by action of tyrosinase enzyme (copper protein complex) in melanoblasts. The melanin gives the brown or black color of the skin, hair and iris. The melanin normally present in the basal cell layer of epidermis, mucous membrane of some breeds of dogs and leptomeninges of calves and lamb.
Hyperpigmentation: It is a pathological increase of the melanin as in case of 1-Melanosis 2-Melanoma 3-Acanthosis nigricans 4-Pigmented moles and freckles.
Hypopigmentation: It is a pathological decrease of melanin as in case of 1-Albinism 2-Leukoderma
3-Vitiligo
Remark: Albinism: It is a hereditary condition associated with an autosomal recessive gene characterized by pathological absence of melanin within an individual. It observed in rats, horse, rabbit, human, cat and dogs. Leukoderma: It is a condition in which some patches of the skin lose its melanin and appear white in color.
Vitiligo: It is a condition in which destruction of melanocytes in small or large circumscribed areas results in patches hyperpigmented border and enlarged slowly. 56
of
depigmentation
and
have
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
N.B: Vitiligines: It is depigmented areas of the skin.
Melanosis Definition: It is deposition of melanin pigment in abnormal sites.
Causes: 1- Congenital as in leptomeninges of calves and lamb. 2- Adrenal diseases and imbalanced hormones. 3- Some neoplasm.
Pathogenesis: Over production of melanin by melanocytes escape of the pigments outside the cells phagocytosis of the pigment by phagocytes (melanophores) Migration to different tissue and organs.
Macroscopic Picture: 1-Brown to black irregular spots on the affected organs 2-When the cut sections immersed in water give ink-like pigment.
Microscopic Picture: 1-Presence of numerous of melanophores in the affected areas filled with melanin. 2-The melanin appears as minute black or brown granules in the cytoplasm of melanophores that overshadow the cell details. 3-No melanoblasts. 4-The melanin is stained black with Fountana’s Silver stain.
Significance: 1-Melanin is harmless and disappeared with age. 2-Melanosis of cornea leads to blindness. 3-Excessive amount of melanin indicates adrenal diseases. 4-Melanotic tumors have economic importance in meat process (unmarketable). Melanoma: It is benign tumor arising from melanoblasts in the epidermis.
Acanthosis nigricans: It is the increase of melanin within the skin of dogs associated with hyperkeratosis.
Pigmented moles and freckles: It is a skin defects in human, where there is focal accumulation of melanin in the skin.
Dopa-Reaction: DOPA = Dioxy-phenylalanine or Dihydroxy phenylalanine. Definition: It is a test, used to determine the presence of melanoblasts. When few sections of affected tissue incubated with DOPA solution give black granular 57
Cellular Adaptation, Injury and Death, Gangrene and PM Changes
precipitation with melanoblasts (melanoma) and negative with melanophores (melanosis). DOPA + Melanoblasts containing tyrosinase enzyme black ppt.
N.B: -The tyrosinase enzyme is absent from melanophores. -Pseudomelanosis: It is post mortem changes due to reaction between Hb and H2S produced by putrefactive bacteria leads to formation of iron sulfide (black). -Mild irritant induces hyperplasia. -Moderate irritant induces inflammation (retrogressive change). -Severe irritant induces necrosis.
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