MORPHOLOGY OF CELLS AND TISSUES REVERSIBLE AND IRREVERSIBLE INJURY.

MORPHOLOGY OF CELLS AND TISSUES REVERSIBLE AND IRREVERSIBLE INJURY.  INTRACELLULAR AND EXTRACELLULAR ACCUMULATION (UPTAKE) OF PROTEINS, HYDROCARBONS AND LIPIDS.

 

Cells and tissue reversible changes occurs in the result of tissue or cell metabolism disturbance  and are accompanied with these substances (proteins, fats, hydrocarbons) which exists as norm intracellular or tissue uptakes and appearance of those pathological which do not exist in the norm.  These changes are named metabolic products pathologic uptakes or dystrophies (from Lat. dys – disturbance, trophe – nutrition). Intracellular uptake of substances causes parenhymatous degenerations development.  Parenhymatous degenerations occurs mostly in highly specialized cells of parenhymatous organs (kidneys, liver, heart, cerebrum, etc.). Acquired or congenital fermentopathies underlie parenhymatous degenerations development. These fermentopathies make a big group of storage diseases or thesaurismoses. Latter contain a big group of storage diseases or  thesaurismoses.

It is useful to describe the basic alterations that occur in damaged cells before we discuss the biochemical mechanisms that bring about these changes. All stresses and noxious influences exert their effects first at the molecular or biochemical level. Cellular function may be lost long before cell death occurs, and the morphologic changes of cell injury (or death) lag far behind bot). For example, myocardial cells become noncontractile after 1 to 2 minutes of ischemia, although they do not die until 20 to 30 minutes of ischemia have elapsed. These myocytes do not appear dead by electron microscopy for 2 to 3 hours, and by light microscopy for 6 to 12 hours.

The cellular derangements of reversible injury can be repaired and, if the injurious stimulus abates, the cell will return to normalcy. Persistent or excessive injury, however, causes cells to pass the nebulous “point of no return” into irreversible injury and cell death. The events that determine when reversible injury becomes irreversible and progresses to cell death remain poorly understood. The clinical relevance of this question is obvious; if we can answer it we may be able to devise strategies for preventing cell injury from having permanent deleterious consequences. Although there are no definitive morphologic or biochemical correlates of irreversibility, two phenomena consistently characterize irreversibility: the inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury, and profound disturbances in membrane function.

 MECHANISMS OF CELL INJURY

Now that we have discussed the causes of cell injury and necrosis and their morphologic and functional correlates, we next consider in more detail the molecular basis of cell injury, and then illustrate the important principles with a few selected examples of common types of injury. The biochemical mechanisms linking any given injury with the resulting cellular and tissue manifestations are complex, interconnected, and tightly interwoven with many intracellular metabolic pathways. It is therefore often difficult to pinpoint specific molecular alterations caused by a particular insult. Nevertheless, several general principles are relevant to most forms of cell injury:

The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. Thus, low doses of toxins or a brief duration of ischemia may lead to reversible cell injury, whereas larger toxin doses or longer ischemic intervals may result in irreversible injury and cell death.The consequences of an injurious stimulus depend on the type, status, adaptability, and genetic makeup of the injured cell. The same injury has vastly different outcomes depending on the cell type; thus, striated skeletal muscle in the leg accommodates complete ischemia for 2 to 3 hours without irreversible injury, whereas cardiac muscle dies after only 20 to 30 minutes. The nutritional (or hormonal) status can also be important; clearly, a glycogen-replete hepatocyte will tolerate ischemia much better than one that has just burned its last glucose molecule. Genetically determined diversity in metabolic pathways can also be important. For instance, when exposed to the same dose of a toxin, individuals who inherit variants in genes encoding cytochrome P-450 may catabolize the toxin at different rates, leading to different outcomes. Much effort is now directed toward understanding the role of genetic polymorphisms in responses to drugs and toxins and in disease susceptibility. The study of such interactions is called pharmacogenomics.Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components The most important targets of injurious stimuli are (1) mitochondria, the sites of ATP generation; (2) cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends; (3) protein synthesis; (4) the cytoskeleton; and (5) the genetic apparatus of the cell.

 

ATP, the energy store of cells, is produced mainly by oxidative phosphorylation of adenosine diphosphate (ADP) during reduction of oxygen in the electron transport system of mitochondria. In addition, the glycolytic pathway can generate ATP in the absence of oxygen using glucose derived either from the circulation or from the hydrolysis of intracellular glycogen. The major causes of ATP depletion are reduced supply of oxygen and nutrients, mitochondrial damage, and the actions of some toxins (e.g., cyanide). Tissues with a greater glycolytic capacity (e.g., the liver) are able to survive loss of oxygen and decreased oxidative phosphorylation better than are tissues with limited capacity for glycolysis (e.g., the brain). High-energy phosphate in the form of ATP is required for virtually all synthetic and degradative processes within the cell, including membrane transport, protein synthesis, lipogenesis, and the deacylation-reacylation reactions necessary for phospholipid turnover. Depletion of ATP to less than 5% to 10% of normal levels has widespread effects on many critical cellular systems .

The activity of the plasma membrane energy-dependent sodium pump is reduced, resulting in intracellular accumulation of sodium and efflux of potassium. The net gain of solute is accompanied by iso-osmotic gain of water, causing cell swelling and dilation of the ER.There is a compensatory increase in anaerobic glycolysis in an attempt to maintain the cell’s energy sources. As a consequence, intracellular glycogen stores are rapidly depleted, and lactic acid accumulates, leading to decreased intracellular pH and decreased activity of many cellular enzymes.Failure of the Ca²⁺ pump leads to influx of Ca²⁺, with damaging effects oumerous cellular components, described below.Prolonged or worsening depletion of ATP causes structural disruption of the protein synthetic apparatus, manifested as detachment of ribosomes from the rough endoplastic reticulum (RER) and dissociation of polysomes into monosomes, with a consequent reduction in protein synthesis. Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes, and the cell undergoes necrosis.

 

Cytosolic free calcium is normally maintained by ATP-dependent calcium transporters at concentrations that are as much as 10,000 times lower than the concentration of extracellular calcium or of sequestered intracellular mitochondrial and ER calcium. Ischemia and certain toxins cause an increase in cytosolic calcium concentration, initially because of release of Ca²⁺ from the intracellular stores, and later resulting from increased influx across the plasma membrane. Increased cytosolic Ca²⁺ activates a number of enzymes, with potentially deleterious cellular effects (Fig. 1-19). These enzymes include phospholipases (which cause membrane damage), proteases (which break down both membrane and cytoskeletal proteins), endonucleases (which are responsible for DNA and chromatin fragmentation), and adenosine triphosphatases (ATPases; thereby hastening ATP depletion). Increased intracellular Ca²⁺ levels also result in the induction of apoptosis, by direct activation of caspases and by increasing mitochondrial permeability. The importance of Ca²⁺ in cell injury was established by the finding that depleting extracellular Ca²⁺ delays cell death after hypoxia and exposure to some toxins.

 

Figure 1-20 The role of reactive oxygen species (ROS) in cell injury. O₂ is converted to superoxide by oxidative enzymes in the endoplasmic reticulum, mitochondria, plasma membrane, peroxisomes, and cytosol.
is converted to H₂O₂ by dismutation and thence to OH^• by the Cu²⁺/Fe²⁺-catalyzed Fenton reaction. H₂O₂ is also derived directly from oxidases in peroxisomes (not shown). Also not shown is another potentially injurious free radical, singlet oxygen. Resultant free-radical damage to lipid (by peroxidation), proteins, and deoxyribonucleic acid (DNA) leads to various forms of cell injury. The major antioxidant enzymes are superoxide dismutase (SOD), catalase, and glutathione peroxidase.

 

Free radicals are chemical species with a single unpaired electron in an outer orbital. Such chemical states are extremely unstable and readily react with inorganic and organic chemicals; when generated in cells they avidly attack nucleic acids as well as a variety of cellular proteins and lipids. In addition, free radicals initiate autocatalytic reactions; molecules that react with free radicals are in turn converted into free radicals, thus propagating the chain of damage. Reactive oxygen species (ROS) are a type of oxygen-derived free radical whose role in cell injury is well established. They are produced normally in cells during mitochondrial respiration and energy generation, but they are degraded and removed by cellular defense systems. When the production of ROS increases or the scavenging systems are ineffective, the result is an excess of these free radicals, leading to a condition called oxidative stress. Cell injury in many circumstances involves damage by free radicals; these situations include ischemia-reperfusion (discussed below), chemical and radiation injury, toxicity from oxygen and other gases, cellular aging, microbial killing by phagocytic cells, and tissue injury caused by inflammatory cells.

 

The accumulation of free radicals is determined by their rates of production and removal. Several reactions are responsible for the generation of free radicals.

The reduction-oxidation (redox) reactions that occur during normal mitochondrial metabolism. During normal respiration, for example, molecular oxygen is sequentially reduced in mitochondria by the addition of four electrons to generate water. In the process, small amounts of toxic intermediate species are generated by partial reduction of oxygen; these include superoxide radicals (
 hydrogen peroxide (H₂O₂), and OH^•. Transition metals such as copper and iron also accept or donate free electrons during certain intracellular reactions and thereby catalyze free-radical formation, as in the Fenton reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + OH^• + O[EEgr ]^–).The absorption of radiant energy (e.g., ultraviolet light, x-rays). Ionizing radiation can hydrolyze water into hydroxyl (OH^•) and hydrogen (H^•) free radicals.The enzymatic metabolism of exogenous chemicals (e.g., carbon tetrachloride; see later)Inflammation, because free radicals are produced by leukocytes that enter tissues Nitric oxide (NO), an important chemical mediator normally synthesized by a variety of cell types , can act as a free radical or can be converted into highly reactive nitrite species

 

Cells have developed many mechanisms to remove free radicals and thereby minimize injury. Free radicals are inherently unstable and decay spontaneously. There are also several nonenzymatic and enzymatic systems that contribute to inactivation of free-radical reactions.

The rate of spontaneous decay of superoxide is significantly increased by the action of superoxide dismutases (SODs) found in many cell types (catalyzing the reaction
2H → H₂O₂ + O₂).Glutathione (GSH) peroxidase also protects against injury by catalyzing free-radical breakdown:
+ 2GSH → 2H₂O + GSSG (glutathione homodimer). The intracellular ratio of oxidized glutathione (GSSG) to reduced glutathione (GSH) is a reflection of the oxidative state of the cell and an important aspect of the cell’s ability to catabolize free radicals.Catalase, present in peroxisomes, directs the degradation of hydrogen peroxide (2H₂O₂ → O₂ + 2H₂O).Endogenous or exogenous antioxidants (e.g., vitamins E, A, and C, and β-carotene) may either block the formation of free radicals or scavenge them once they have formed.As mentioned above, iron and copper can catalyze the formation of ROS. The levels of these reactive metals are reduced by binding of the ions to storage and transport proteins (e.g., transferrin, ferritin, lactoferrin, and ceruloplasmin), thereby decreasing the formation of ROS.

 

Lipid peroxidation of membranes. Double bonds in membrane polyunsaturated lipids are vulnerable to attack by oxygen-derived free radicals. The lipid-radical interactions yield peroxides, which are themselves unstable and reactive, and an autocatalytic chain reaction ensues.Cross-linking of proteins. Free radicals promote sulfhydryl-mediated protein cross-linking, resulting in enhanced degradation or loss of enzymatic activity. Free-radical reactions may also directly cause polypeptide fragmentation.DNA fragmentation. Free-radical reactions with thymine iuclear and mitochondrial DNA produce single-strand breaks. Such DNA damage has been implicated in cell death, aging, and malignant transformation of cells.

 

 Mechanisms of membrane damage in cell injury. Decreased O₂ and increased cytosolic Ca²⁺ are typically seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which are often produced on reperfusion of ischemic tissues, also cause membrane damage (not shown).

 

Early loss of selective membrane permeability leading ultimately to overt membrane damage is a consistent feature of most forms of cell injury (except apoptosis). The plasma membrane can be damaged by ischemia, various microbial toxins, lytic complement components, and a variety of physical and chemical agents. Several biochemical mechanisms may contribute to membrane damage:

Decreased phospholipid synthesis. The production of phospholipids in cells may be reduced whenever there is a fall in ATP levels, leading to decreased energy-dependent enzymatic activities. The reduced phospholipid synthesis may affect all cellular membranes including the mitochondria themselves, thus exacerbating the loss of ATP.Increased phospholipid breakdown. Severe cell injury is associated with increased degradation of membrane phospholipids, probably due to activation of endogenous phospholipases by increased levels of cytosolic Ca²⁺.ROS. Oxygen free radicals cause injury to cell membranes by lipid peroxidation, discussed earlier.Cytoskeletal abnormalities. Cytoskeletal filaments serve as anchors connecting the plasma membrane to the cell interior. Activation of proteases by increased cytosolic Ca²⁺ may cause damage to elements of the cytoskeleton.Lipid breakdown products. These include unesterified free fatty acids, acyl carnitine, and lysophospholipids, catabolic products that are known to accumulate in injured cells as a result of phospholipid degradation. They have a detergent effect on membranes. They also either insert into the lipid bilayer of the membrane or exchange with membrane phospholipids, potentially causing changes in permeability and electrophysiologic alterations.

 

The most important sites of membrane damage during cell injury are the mitochondrial membrane, the plasma membrane, and membranes of lysosomes.

Mitochondrial membrane damage. As discussed above, damage to mitochondrial membranes results in decreased production of ATP, culminating iecrosis, and release of proteins that trigger apoptotic death.Plasma membrane damage. Plasma membrane damage leads to loss of osmotic balance and influx of fluids and ions, as well as loss of cellular contents. The cells may also leak metabolites that are vital for the reconstitution of ATP, thus further depleting energy stores.Injury to lysosomal membranes results in leakage of their enzymes into the cytoplasm and activation of the acid hydrolases in the acidic intracellular pH of the injured (e.g., ischemic) cell. Lysosomes contain RNases, DNases, proteases, glucosidases, and other enzymes. Activation of these enzymes leads to enzymatic digestion of cell components, and the cells die by necrosis.

 

Cells have mechanisms that repair damage to DNA, but if this damage is too severe to be corrected (e.g., after radiation injury or oxidative stress), the cell initiates its suicide program and dies by apoptosis. A similar reaction is triggered by improperly folded proteins, which may be the result of inherited mutations or external triggers such as free radicals. Since these mechanisms of cell injury typically cause apoptosis, they are discussed later in the chapter.

 

Different injurious stimuli may induce death by necrosis or apoptosis As mentioned above and detailed later, severe depletion of ATP and loss of membrane integrity are typically associated with necrosis. Apoptosis is an active and regulated process not associated with ATP depletion and it has many unique features, which we will describe separately later in the chapter. 

The two main morphologic correlates of reversible cell injury are cellular swelling and fatty change. Cellular swelling is the result of failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis. Fatty change occurs in hypoxic injury and various forms of toxic or metabolic injury, and is manifested by the appearance of small or large lipid vacuoles in the cytoplasm. It occurs mainly in cells involved in and dependent on fat metabolism, such as hepatocytes and myocardial cells. The mechanisms of fatty change are discussed later in the chapter. 

Causes of metabolism products abnormal uptake

1 Cell pathology. Cells are not able to utilize substances as energy or plastic material  or release them. This is caused mostly by cells structure injury with various factors, sometimes by congenital or acquired ferments pathology, which participate in metabolism   (fermentopathies).

2  Function disturbance of transport systems, providing both substances supply to tissues and cells and metabolism products excretion. It is often observed under cardiovascular collapse and pulmonary insufficiency.  

3 Endocrine and nervous regulation of trophism disorders. 

Mechanisms of metabolism products abnormal uptake Infiltration  is excessive penetration of metabolism products from blood into cells and intercellular substance with their subsequent uptake due to ferment system, providing their metabolism, insufficiency. Substances metabolism products abnormal uptake by way of infiltration is observed in liver, kidneys, aorta wall.  

Decomposition (phanerosis) occurs under cell and intercellular substance ultrastructures destruction due to intoxication,  hypoxia or other reasons. Ultrastructures membranes are made of proteins, fats and hydrocarbons, so under their destruction these substances are accumulated and stored in cells. 

Distored synthesis is synthesis of those substances in cells and tissues which are not observed in them as a norm. As an example, it’s glycogen synthesis iephron tubules epithelium under diabetes mellitus,  alcohol hyaline synthesis in hepatocytes. 

Transformation is the creation of one kind of metabolism products from intermediate disintegration products, which should be utilized for proteins, fats and hydrocarbons synthesis.  For example, it’s fats and hydrocarbons components transformation into proteins under starvation, fats and hydrocarbons components transformation

into glycogen under diabetes mellitus. 

Metabolism products abnormal uptake classification

Classification by the kind of metabolism disturbance prevail:

a) protein,  b) fat, c) hydrocarbon,  d) mineral

By pathologic process localization:

a) parenchymatous (modifications in the organs parenchymatous cells –  cardiomyocytes,  hepatocytes, ganglionic cells of cerebrum, etc.);

b) stromal-vascular (modifications in organs stroma);

c) mixed (changes in parenchyma and stroma).

Depending on genetic factors influence:

a)  congenital,  b)  acquired.

By process spread:

a) general, b) local.

Morphology of proteins abnormal uptake (proteinosis)

        Occurs under proteins metabolism disturbance. Tissues proteins form cells as plastic materials  (capsule, nucleus, cytoplasm, intracellular organelles) as well as intercellular stroma  – collagen, elastic, reticulin fibers,  basic intercellular substance,  vessels, nerves.  By proteins metabolism disturbance development location proteinosises are divided into  parenchymatous, stromal-vascular and mixed.  .

Under parenchymatous proteinosis physical–chemical features of intracellular proteins are violated.  At the beginning grain effect occurs in cytoplasm at the cost of protein inclusions, which is manifestation of cell ultrastructures overstrain (hyper function).  This process is reversible. Quite often proteins disbolism is combined with Na–K–pump operation faults, which is accompanied with natrium ions uptake and cells hydration.  In case intoxication, hypoxia, inflammation or other reasons of proteinosis increase this cause cells destructive changes intensification. The following kinds of   parenchymatous proteinaceous degenerations (proteinosis) are recognized: hyaline-drop, hydropic (vacuolar), keratinization. 

At hyaline–drop proteinosis  proteins compacts and become similar to hyaline cartilage. Big hyalinoid drops of protein occur in cells cytoplasm. Sometimes coagulatioecrosis develops and cells die, organ function decreases, but macroscopic changes are not found. This kind dystrophy is often observed in hepatocytes under alcoholic hepatitis (Mellori bodies), in renal tubules epithelium under nephrotic syndrome, etc. 

Cytoplasmic organelle damage leads to a variety of injury patterns, most of which are best seen by electron microscopy. Acute injuries tend to damage an entire cell, so specific organelle damage is beside the point. However, in some cases the damage can be cumulative over many years. Here are Mallory bodies (the red globular material) composed of cytoskeletal filaments in liver cells chronically damaged from alcoholism. These are a type of “intermediate” filament between the size of actin (thin) and myosin (thick).

Intracellular accumulations of a variety of materials can occur in response to cellular injury. Here is fatty metamorphosis (fatty change) of the liver in which deranged lipoprotein transport from injury (most often alcoholism) leads to accumulation of lipid in the cytoplasm of hepatocytes.

Hydropic or dropsy proteinosis  is characterized by intracellular fluid increase, in which cytoplasm proteins are dissolved due to hydrolytic pigments action. Vacuoles full of cytoplasm fluid occur in cells. Further on cells cytoplasm transforms into blisters full with fluid, intracellular organelles destroy, cell dies off and coliquation necrosis  develops. Organs also didn’t change macroscopically.  Hydropic proteinosis often develops in liver under viral hepatitis, in kidneys under glomerulonephritis, etc. 

Sometimes cellular injury can lead to accumulation of a specific product. Here, the red globules seen in this PAS stained section of liver are accumulations of alpha-1-antitrypsin in a patient with a congenital defect involving cellular metabolism and release of this substance.

Many inherited disorders of metabolism involving enzymes in degradation pathways can lead to accumulation of storage products in cells, as seen here with Gaucher disease involving spleen. The large pale cells contain an accumulated storage product from lack of the glucocerebrosidase enzyme.

The yellow-brown granular pigment seen in the hepatocytes here is lipochrome (lipofuscin) which accumulates over time in cells (particularly liver and heart) as a result of “wear and tear” with aging. It is of no major consequence, but illustrates the end result of the process of autophagocytosis in which intracellular debris is sequestered and turned into these residual bodies of lipochrome within the cell cytoplasm.

Keratinization proteinosis  is characterized with excessive keratin generation on the surface of plane keratinized epithelium – hyperkeratosis, ichthyosis. The causes of keratinization development is chronic inflammation, avitaminosis, skin development abnormalities.   Leukoplakia which is mucous tunics epithelium pathologic keratinization, also belongs to this process and can become a source of malignant growth.

Extracellular uptakes

Extracellular uptakes occur in the result of metabolism disturbance in organs stroma or in vessels walls, so they are named stromal–vascular or mesenchymal proteinosis.  Important attention is paid to proteinosis developing in the result of proteins metabolism in conjunctive tissue and are found in stroma and vessels walls. Primary pathologic changes are developed on histion level, consisting of microcirculation channel: basic substance, fibers (collagen, reticulum, elastic), cells (fibroblasts, fibrocytes, lymphocytes,  labrocytes, histiocytes), nerves. Basic substance is connecting, cementing, fiber and cells are situated in it. By chemical composition it is polymer of composite protein-hydrocarbon molecules – mucopolysaccharides (glycosamineglycanes).  The following relates to stromal–vascular proteinosis:  mucoid swelling, fibrinoid swelling (fibrinoid), hyalinosis, which are considered to be consequent stages of conjunctive tissue destruction.

Mucoid swelling  – is primary disorganization of conjunctive tissue.  Causes: hypoxia, allergy, endocrine pathologies.  It often occurs under  rheumatic and infection diseases, atherosclerosis, it is found in  artery walls, cardiac valves, endocardium, heart. Basic substance  depolymerization underlies its development.   As a consequence it becomes hydrophilic, attracts liquid, vessel wall penetrability increases. Basic substance hydration, collagen fibers swelling occurs. With vascular-tissue penetrability growth conjunctive tissue saturates with blood plasm proteins, in first turn with albumines and globulins.   Macroscopically organ or tissue mostly doesn’t change. Microscopically phenomenon of   metachromasia is observed: glycosamineglycanes are painted with toluidine blue in red color. Described changes in conjunctive tissue provided that the reason was eliminated are reversible and tissue structure is rehabilitated. 

This Congo red stain reveals orange-red deposits of amyloid, which is an abnormal accumulation of breakdown products of proteinaceous material that can collect within cells and tissues.

Fibrinoid swelling is following stage of conjunctive tissue disorganization. Under substantial growth of vascular-tissue penetrability fibrinogen sweats in stroma from  vessels clearance, which rather quickly precipitates in strings of fibrin, collagen fibers are destroyed (broken, fragment), conjunctive tissue basic substance chemical composition is changed. Under fibrinoid swelling deep and irreversible disorganization of conjunctive tissue is observed, which is accompanied with basic substance and fibers destruction  against the background of considerable increase of balls vascular permeability. Macroscopically  organ doesn’t change, microscopically  collagen fibers become homogenous,  eosinophilic, becomes yelow when painted with  picrofuchsin, pyroninophil and argyrophil. Consequence Fibrinoid necrosis is developed in the final of the process.  Significance – organ function disturbance under heart disease  formation, joints immobility,  luminal narrowing and vessel wall elasticity decrease, organ function termination under renal insufficiency at malignant hypertension, when fibrinoid changes as well as arterioles and cappilars necrosis develops. 

Hyalinosis is the final stage of tissue disorganization and is characterized with uptake of collagen destruction products, plasm proteins, polysaccharides, which merge into homogenous mass which consolidates as time passes, becomes semi–transparent similar to hyaline cartilage, so it is called hyaline. This is complex fibrillar protein. Hyalinosis occurs as a consequence of fibrinoid swelling,  plasmorrhagia, sclerosis, necrosis. It develops as the result of peculiar completion of sclerosis in scarring, cardiac valves under rheumatism (local conjunctive tissue hyalinosis). Macroscopically fibrous conjunctive tissue becomes dense, cartilaginous, whitish, semi-transparent.  Microscopically collagen fibers loss fibrillarity and merge into homogenous dense cartilaginous mass, cells squeeze and atrophy.  

Heart in such cases is enlarged, ventricular cavities are dilated, mitral valve flappers are dense, whitish color, conjoint in between each other, considerably deformed. This kind of hyalinosis is peculiarly expressed in rough vicious cicatrix after burns (keloid). Consequences are unfavorable because of considerable deterioration of organ or injured tissue function.  

Systemic hyalinosis develops in vessels walls under hypertension disease, diabetes mellitus (vascular hyalinosis) and is mostly expressed in kidneys, cerebrum, eye retina, pancreas. Considering occurrence pathogenesis three kinds of vascular hyaline are recognized: simple is observed under hypertension disease,  atherosclerosis; lipohyaline is developed under diabetes mellitus; complex hyaline occurs in the result of  immunopathologic disturbances and vessel wall fibrinoid disorganization at collagenosis. 

Morphology of lipids pathological uptake (lipidosis)

Occurs as the result of fats metabolism disturbance. 

Lipidosis are divided into parenchymatous and stromal-vascular (mesenchymal) fatty (adipose) degenerations. To reveal fats frozen sections are colored with  sudan ІІІ or ІV.

Parenchymatous lipidosis are manifested with neutral lipids (triglycerides) drops uptake in cells cytoplasm  and are the results of cytoplasm fats metabolism disturbance. Mostly they are found in myocardium, lever, kidneys.  

Myocardium lipidosis  is characterized with lipoproteids drops uptake in cardiac hystiocytes. As a rule it is observed under intoxications (diphtherial, alcohol, with   phosphoric compounds, arsenic, diseases of liver, kidneys, thyrotoxicosis, etc.), long time general hypoxia  (anemia, chronic pulmonary and cardiovascular insufficiency), Under oxygen deficiency process of oxidative phosphorylation and ATP synthesis in cardiomyocytes decreases,  fatty acids beta-oxidation violates. So fats coming into cell are not completely utilized as plastic and power material and they accumulate in cytoplasm. Besides that under hypoxia membrane lipoprotein complexes destruction is observed (decomposition or phanerosis). Macroscopically heart at this process enlarges in size,  its chambers stretch, myocardium becomes  flaccis, of clay-yellow color, retraction ability of cardial muscle decreases. From myocardium side especially on papillary muscles surface, trabeculas, it is observed yellow-grey striation– “ tiger heart”, which is caused by dystrophy. Microscopically fat uptakes in muscular cells groups, situated  downstream cappilars venous elbow and small veins where hypoxia factor is mostly expressed. 

Liver lipidosis is characterized with fat content increase in hepatocytes. Quite often it is the result of imbalance between increased fats supply under hyper lipidemia (alcoholism, diabetes mellitus, general obesity), their decreased        assimilation  (fatty acids oxidation in mitochondrions under hypoxia or toxic influences)  and lipids excretion decrease by liver cells under apoprotein production decrease which transports fats in the form of lipoproteins. This is observed in case protein insufficiency in food or under gastrointestinal disturbances, poisoning with  ethanol, phosphor, etc., congenital defects of ferments metabolizing fats.  Microscopically first occurs saw type, then small drop and large drop degeneration. Three stages of liver lipidosis are distinguished:  

1- fat uptake in hepatocytes,  2- fat uptake with  mesenchymal reaction development, 3- fat uptake with liver fibrosis and cirrhosis development.  Fat fills all cytoplasm and gradually pushes nucleus aside to periphery and modified hepatocytes becomes similar to  adipocytes. Fatty degeneration  prevalence in peripheral portions of liver part confirms infiltration mechanism of its development, which is observed under  hyperlipidemia.  Fatty degeneration development prevalence in central portions of liver part is connected with decompensation mechanism and is observed under hypoxia or intoxication.  Macroscopically   liver is enlarged,  loose   (of pastry consistency), yellow or clay color. 

Kidneys lipidosis is often observed under nephrotic syndrome,  chronic renal insufficiency when hyperlipidemia and lipiduria occur.  Fat excess is excreted from organism with kidneys and constipates them.   Microscopically fat occurs in proximal, distal or convoluted renal tubules epithelium in cells basal portions.   Nephrocytes lipidosis often joins hyaline-drop degeneration and hydropic proteinosis.   Macroscopically  kidney is enlarged, flaccid, cortical layer is dilated with signs of swelling, of grey color with yellow specks.   

Congenital lipid metabolism disturbances are manifested with systemic lipidosis and pertain to fermentopathies (diseases of storage or uptake). The following diseases are marked out: cerebrosine lipidosis (Gaucher’s disease),  sphingomyelin lipidosis (Niemann-Pick disease), generalized gangliosidosis (Tay-Sachs disease), generalized gangliosidosis (Norman-Landig disease), which are accompanied with liver, spleen, marrow, nervous system and other organs and tissues damage.  

Stromal–vascular lipidosis include neutral fat metabolism disturbance in adipose tissue and adipose depot as well as cholesterol and its ethers in arteries walls under atherosclerosis. 

General disturbance of neutral fats metabolism is manifested with neutral fat stocks increase or decrease in hypodermic fat tissue, mesentery, pericardium, marrow, etc.  General uptake of neutral fat in fat depots is called obesity.   The following is recognized: primary or idiopathic obesity  the cause of which is unknown and  secondary obesity which occurs under endocrine, cerebral and hereditary diseases. By external signs obesity kinds are as follows:  upper, mid, lower and universal symmetric. By morphologic signs hyper plastic type is marked out characterized with fat cells (adipocytes) quantity increase in organism as well as  hypertrophic   (malignant) type the basis of which is adipose cells size increase several times and triglycerides content increase in cytoplasm several times. 

Under general obesity the important clinical attention is paid to heart injury.  In this case adipose tissue grows under pericardium,  surrounding organ like case.  Lipocytes uptake in myocardium stroma between cardiac hystiocytes,   squeezing the latter ones which causes their atrophy. Right portion of the heart is the most injured one.  Sometimes the whole thickness of right ventricle myocardium is changed with adipose tissue,  that can  cause cardiac rupture or accelerate decompensation process. 

Neutral fat local uptake   is observed under  Madelung’s syndrome, Dercum’s disease  and Weber-Krischen’s desease, as well as   vacant obesity when organ atrophied portion is substituted.  The essence of Dercum’s disease  is in painful lipomas occurrence in subcutaneous adipose tissue of extremities and trunk. Weber-Krischen’s disease is characterized with recurrent nonpurulent cellulites with productive granulomatous inflammation development around sphacelous adipose tissue.  

General decrease of adipose tissue  occurs under emaciation (cachexia). Tissue becomes loose, flabby, is saturated with liquid, sliming. 

Cholesterol and its ethers’ metabolism imbalance is a basis of atherosclerosis development. Uptake of cholesterol fractions,  lipoproteins of various density, proteins in arteries’ walls causes  formation of fat detritus  (atheroma) and conjunctive tissue enlargement (sclerosis). Hereditary cholesterol metabolism disturbance is observed under family  hypercholesterolemic xanthomatosis, manifested with xanthalasms formation (cholesterol deposition in skin, big vessels’ walls, heart valves and other organs).

Carbohydrates pathologic uptake (glycogenosis) morphology 

The most valuable in carbohydrates metabolism disturbance is glycogen, glycosamineglycanes and  glycoproteins.  The most important in this pathology is glycogen metabolism disturbance occurring under diabetes mellitus. In case insulin deficiency in blood the tissues utilize sugar insufficiently causing sugar level increase in blood (hyperglycemia), and glycogen quantity in tissues decreases. Kidneys remove sugar excess with urine (glucosuria). In the result of glucose polymerization under its resorption from plasma ultrafiltrate  glycogen is accumulated in   tubules epithelium, mesangium and membranes of glomerule vessels. The most of it is in epithelial cells and in Henle’s loop lumens (narrow segment). Epithelium in these sections of nephron becomes high, with light and foamy cytoplasm. Changes in kidneys under diabetes mellitus are finalized with sclerosis development called diabetic glomerulosclerosis.

Hereditary (glycogenosis) occurs under deficiency of ferment which splits glycogen and the latter accumulates in cells.  These includes hepatorenal glygenosis, Pompe disease, MacArdles and Gerce’s  under which glycogen structure is not damaged,  as well as Forbes-Cori (type 3 glycogenosis) and Anderson’s disease (type 4 glycogenosis) under which this structure is changed.

Under glycoproteins metabolism  disturbance (mucins and mucoids which are the base of  mucus) mucus degeneration develops.  The typical manifestation of it is  mucoviscidosis which is  systemic disease, charactristic of which is  high viscosity of mucus,  causing development of retention cysts and sclerosis in  pancreas, bronchi,  digestive and other glands.  Besides that this degeneration is often observed under  catarrhal inflammation of nose mucous tunic (rhinitis),  mucous tunic of larynx  (laryngitis), bronchi  (bronchitis), stomach (gastritis), etc.  Macroscopically excess of mucus is seen on mucous tunic, and this mucous trickles down from the surface. Microscopically wine glass like cells appear in mucous tunic and release mucus.  Also desquamation or cells necrosis is observed,    glands’ excretory ducts are clogged with mucus which is accompanied with cysts formation.

Glycoproteins and glycosamineglycanes uptake in organs’ stroma is accompanied  with collagen fiber as well as cartilage and adipose tissue substitute with mucus-like mass.  Damaged tissues cells have star-like shape.  This process is called tissue sliming and it is observed under  cachexias and  myxedema. Carbohydrates uptake consequence can be reversible and under process progress they become semi–transparent, looks like mucus,  colliquative necrosis develops.

Metabolic disease. Morphology of pathologic accumulation of endogenous and exogenous pigments.

Morphology of mineral metabolism disease

Importance of the topic: metabolic disease rather often occurs in practice of clinicians and should be considered as a manifestation of general pathologic processes. Often it occurs at endocrine diseases, as well as at pathology of gastrointestinal tract  and hepatobiliary system and  it reveals through structural morphologic changes. Knowledge of issues of this topic enlarges the minds of would-be clinicians concerning the kind of changes that underlie various pathologic processes at one or another disease.

Purpose: to study causes, development mechanism, morphologic manifestations and consequences of accumulation of endogenous and exogenous pigments, as well as mineral metabolism disease.

Specific goals: 1 To learn varieties of  metabolic diseases and their development mechanisms.

2  To study causes, development mechanism, pathogenesis and morphogenesis, morphologic presentations and consequences of accumulation of endogenous and exogenous pigments, as well as mineral metabolism disease.

3 To learn to differentiate various kinds of pigment metabolic diseases and mineral metabolism diseases according to morphologic signs.

4  To evaluate functional importance and consequences of accumulation of endogenous and exogenous pigments, as well as mineral metabolism diseases, to know how to diagnose their morphologic manifestations in cells and tissues.

Iron metabolic disease and metabolic disorder of hematogenous pigments. Metabolism and pathogenic action  of iron, formation of anabolic and catabolic ferritin. Classification of hematogenous pigments. Toxic forms of ferritin: causes and consequences of their formation.

        Hemosiderosis (topical and extensive): causes, pathogenesis, morphologic characteristics  and consequences. Acquired and congenital hemochromatosis: morphologic characteristics  and consequences.

        Hematoidin, hematin, porphyrin: features and area of formation, morphologic characteristics and consequences of their accumulation.

        Bilirubin metabolic disease: causes, pathogenesis and anatomical pathology of hemolytic jaundice, hepatic jaundice, obstructive jaundice. Pathogenic effect of increased bilirubin, complications and causes of death at jaundice.

        Melanin formation disorder. Causes, pathogenesis, morphologic characteristics   of hypopigmentation (leukoderma, vitiligo, albinism) and hyperpigmentation (common melanoderma, local melanosis, pigmented nevus).

        Nucleoprotein metabolic disease. Podagra and gouty arthritis: classification, aetiology, pathogenesis, stage of disease  and morphologic characteristics  of joints’ changes, clinical presentations, complications and consequences. Podagric nephropathy. Clinicopathologic characteristics.

        Copper metabolic disease. Hepatolenticular degeneration (Wilson’s disease).

        Potassium metabolic disease. Periodic paralysis.

        Calcium metabolic disease. Acute hypocalcemia and hypercalcemia: definition,  pathogenesis, consequences and their role in thanatogenesis. Calcinosis (calcification): definition, classification, morphogenesis of metastatic calcification, dystrophic calcification and metabolic calcinosis; consequences, the role of calcification of organs in thanatogenesis.

        Stone formation: localization, causes, pathogenesis, types of stones, consequences and complications of  stone formation.

 

 Auxiliary materials for self-training to practical lesson

Pathologic accumulation of endogenous pigments rather often is represented in metabolic disease of complex proteins – chromoproteins, nucleoproteins, glucoproteins and lipoproteins. Chromoproteins, or colored proteins, are endogenous pigments, to which hematogenous, proteinogenous and lipidogenous pigments are referred. Metabolic disease of complex proteins is observed in parenchyma, as well as in stroma of tissues and organs.

Iron metabolic disease and metabolic disorder  of hematogenous pigments

Ferritin, hemosiderin, bilirubin are referred to hematogenous pigments. There are pigments which may be accumulated in organism at physiological conditions and at some diseases; hematoidin, hematin, porphyrin are pigments which are formed only at pathologic processes. They are generated  from hemoglobin at destruction (hemolysis) of erythrocytes.

Ferritin  is generated from hemoglobin at intensive intravascular hemolysis of erythrocytes – catabolic form. Anabolic form is  generated from iron absorbed in bowels . At conditions of  hypoxia ferritin is restored into an  active form (SH-ferritin) which is an adrenalin antagonist, that’s why it acts  vasoparesically, i.e. as vasodilator. An active ferritin is accumulated at incompatible blood transfusion and collapse of vessels is observed, then a  syncope takes place.

Hemosiderin is generated from hemoglobin only  in macrophages (intracellularily). It appears outside the cell only after cell destruction. It looks like small brown seeds; tissue acquires brown coloration at evident hemosiderosis. One can distinguish common and topical hemosiderosis.  Common hemosiderosis is developed at intensive intravascular hemolysis of erythrocytes (incompatible blood transfusion, hemolytic poisoning). Unconjugated hemoglobin is captured by macrophages of unitary mononuclear phagocyte system of liver, spleen, lymph nodes, bone marrow, thymus gland in which hemoglobin turns into hemosiderin. Listed organs acquire brown coloring.

Topical hemosiderosis  arises at areas of extravasation.  Erythrocytes  are  absorbed outside the vessels by macrophages, in which hemoglobin turns into  hemosiderin.  An example of topical hemosiderosis is pulmonary hemosiderosis which is developed at venous plethora of lungs accompanied by diapedetic extravasations.

Hemochromatosis  is a peculiar disease closely related to common hemosiderosis. There could be primary  and secondary one.  Primary (hereditary) hemochromatosis is referred to storage diseases, caused by a hereditary defect of small intestine ferments.  A secondary one is conditioned by acquired enzymatic deficiency of  systems providing food iron metabolism.

A Prussian blue reaction is seen in this iron stain of the liver to demonstrate large amounts of hemosiderin that are present within the cytoplasm of the hepatocytes and Kupffer cells. Ordinarily, only a small amount of hemosiderin would be present in the fixed macrophage-like cells in liver, the Kupffer cells, as part of iron recycling.

The brown coarsely granular material in macrophages in this alveolus is hemosiderin that has accumulated as a result of the breakdown of RBC’s and release of the iron in heme. The macrophages clear up this debris, which is eventually recycled.

Bilirubin is a bile pigment generated at destruction of hemoglobin  and detachment of haem in reticulum- endothelial (mononuclear) system. Increased  bilirubin (bilirubinhemia) is evidence of jaundice. One can distinguish hemolytic jaundice, hepatocellular jaundice and obstructive (mechanical) jaundice. Hemolytic jaundice arises at infectious diseases, intoxications, isoimmune and autoimmune conflicts, massive hemorrhage, as well as erythrocytopathy and hemoglobinopathy.

Hepatocellular jaundice arises at liver diseases of various aetiology, in case defective hepatocytes are not able to capture bilirubin, its conjugation to glucuronic acid and excretion are disturbed. Obstructive (mechanical) jaundice arises at retention  of  bile outflow from liver.

These renal tubules contain large amounts of hemosiderin, as demonstrated by the Prussian blue iron stain. This patient had chronic hematuria.

Hematoidin is a pigment which doesn’t contain iron. It is accumulated in central areas of  hemorrhage in the distance of living tissues.

Hematin – is an oxidized form of haem. The following pigments are referred to: malarial pigment which is generated from hemoglobin under influence of malarial plasmodia, muriatic hematin which is generated at hemoglobin interaction with intestinal juice ferments and hydrochloric acid (it colours erosions and bottom of bleeding ulcer into black and brown), as well as formalin pigment which occurs in histologic specimen fixed by acid formalin.

The yellow-green globular material seen in small bile ductules in the liver here is bilirubin pigment. This is hepatic cholestasis.

The black streaks seen between lobules of lung beneath the pleural surface are due to accumulation of anthracotic pigment. This anthracosis of the lung is not harmful and comes from the carbonaceous material breathed in from dirty air typical of industrialized regions of the planet. Persons who smoke would have even more of this pigment.

Hematoporphyrin is a pigment which is melanin antagonist. Its small quantity is contained in blood, urine and stool, it heightens light sensibility of  skin. Excess accumulation of this pigment is called porphyria. It could be caused by congenital defect of porphyrin metabolism or acquired one: lead  or barbiturate poisoning, avitaminosis PP, etc. Such patients are UV hypersensitive which causes burns, ulcers, skin atrophy and depigmentation. Bones and teeth are coloured into brown.

Metabolic disorder  of proteinogenous pigments.

 Melanin chromogenesis disorder.

Melanin, as well as adrenochrome and pigment of enterochromaffin cell granules are referred to proteinogenous (tyrosinogenous) pigments which are tyrosine and  tryptophan metabolic derivatives.

Melanin is a brown–black pigment which determines color of skin, hair and eyes. Melanin chromogenesis disorder could appear in increase or decrease of this pigment in skin. There could be local or extensive process. There could be congenital or acquired pathology.  Extensive hypopigmentation or hypomelanosis (albinism) appears as a result of hereditary deficiency of  tyrosinase. Local hypomelanosis (vitiligo, leukoderma) appears as a result of disorder of neuroendocrine control of melanogenesis at leprosy, diabetes mellitus, hyperparathyroidism, Hashimoto’s thyroiditis, syphilitic skin affection. Extensive acquired hypermelanosis declares itself in excessive accumulation of melanin in skin (melanoderma) and is observed  at emaciation, Addison’s disease, endocrine disorders, pellagra, scurvy. Extensive congenital hypermelanosis declares itself in spotted skin pigmentation, hyperkeratosis and edema – pigmentary xeroderma. Local congenital hypermelanosis is represented by birthmarks or nevus, acquired one is observed at pregnancy, pituitary adenoma, lentigo, melanosis coli at constipation.

Adrenochrome is an  adrenalin oxidation product. It occurs in the form of granules in cells of medullary substance of adrenal glands.

Pigment of enterochromaffin cell granules occurs in cells of diffuse endocrine system: enterochromaffin cells of stomach, bowels, B and C cells of thyroid gland, cells of juxtaglomerular apparatus of kidney, cells of Langans’s islands of pancreas. It is considered to be a serotonin analog. Carcinoids or tumors made of above mentioned cells possess a significant serotonin activity. In such cases patients get carcinoid syndrome.

Here is anthracotic pigment in macrophages in a hilar lymph node. Anthracosis is nothing more than accumulation of carbon pigment from breathing dirty air. Smokers have the most pronounced anthracosis. The anthracotic pigment looks bad, but it causes no major organ dysfunction.

Metabolic disorder  of lipidogenous pigments

Lipofuscin  and lipochromes are referred to lipidogenous pigments.

Lipofuscin is a pigment of goldish colour. Its perinuclear location is an evidence of active metabolic processes. Its accumulation (lipofuscinosis) at the periphery of a cell is an evidence of activity decrease of respiratory ferments in a cell. Lipofuscinosis is occurred at aging, cachexy. The organs are colored into brown – brown atrophy of myocardium, liver.

Lipochrome colours lipocytes,  adrenal gland cortex, blood serum, yellow body of ovary  into yellow. At pathologic conditions the quantity of lipochromes is increased in fatty tissue at diabetes mellitus, lipidic-vitaminous metabolic disorder, drastic emaciation.

Metabolic disorder  of nucleoproteids

It could be often observed at excessive formation of  uric acid and its salts which determines development of podagra, urolithiasis, uric acid infarct. At most cases pathology is determined by congenital purine metabolic disorder. Over-use  of animal proteins, kidney diseases are of a significant importance for disease pathogenesis. Uric acid  sodium deposits in joints (synovial membrane, articular cartilages of hands and feet), synovial membranes of tendon with necrosis areas developed, granulomatosis giant-cell reaction, painful arthroliths, deformation of joints are typical for podagra and gouty arthritis. Podagric nephropathy – uric acid  salt deposits in ducts and gathering tubes with obstruction of their lumens and inflammatory,  sclerotic and atrophic changes – arises as complication.

Copper metabolic disorder

        It could be most often observed at hereditary hepatolenticular degeneration or  Wilson‘s disease. Copper accumulation is observed in liver, brain, kidneys, pancreas,

Potassium metabolic disorder  cornea – typical green-brown Kaiser- Fleischer ring at the periphery of cornea. Dystrophic and sclerotic changes are the result of copper accumulation in organs.

It could declare itself in increase of potassium in blood and tissues which is observed at Addison’s disease as  result of affection of adrenal glands. Decrease of potassium causes periodic paralysis – fit of weakness and motor paralysis development.

Calcium metabolic disorder

It could declare itself in increase or decrease of calcium concentration in blood (hypocalcemia and hypercalcemia). Calcium metabolic disorder  results in development of calcifications (calcinosis) – calcium salts deposits in intercellular substance or cells, that’s why calcifications are divided into intercellular and extracellular ones. According to development mechanism there are metastatic, dystrophic, metabolic calcifications. Calcifications also could be systemic or local.

Metastatic calcifications are more often systemic and appear at hypercalcemia caused  by the following:

–                  disorder of endocrine control of calcium metabolism (hyperproduction of parathyroid hormone, calcitonin deficiency), excessive vitamin D content;

–                   intensive calcium excretion from bones (multiple fractures, myelomatosis, tumor deposits of bones, osteomalacia, hyperparathyroidic osteodystrophy);

–                  disorder of calcium excretion from organism (colonic involvement, chronic dysentery, mercuric chloride poisoning, kidney diseases: polycystic renal disease, chronic nephritis).

Most often there are calcium salts deposits in lungs, mucous coat of stomach, kidneys, miocard, walls of arteries.

This is dystrophic calcification in the wall of the stomach. At the far left is an artery with calcification in its wall. There are also irregular bluish-purple deposits of calcium in the submucosa. Calcium is more likely to be deposited in tissues that are damaged.

Here is so-called “metastatic calcification” in the lung of a patient with a very high serum calcium level (hypercalcemia).

Dystrophic calcifications or petrifications are of local character and result in calcium salts deposits formation iecrosis areas or areas of severe dystrophic changes of tissues (tuberculosis, gumma, infarction, atherosclerosis of vessel wall, mitral valve at endocarditis, dead parasites).

Change of physicochemical  composition of tissues and local increase in phosphatase activity determine their development, there is no hypercalcemia observed at the same time.

Metabolic calcinosis appears at instability of buffer systems of organism (calcium gout, interstitial calcinosis). Consequences of calcifications are unfavorable in most cases.

Stone formation  is appearance of solid concrements in caval organs or excretory ducts of glands.  Stones appear in biliary and urinary tracts, excretory ducts of pancreas and salivary glands, bronchi and bronchiectasis, as well as in vessels and bowels. Stone formation is caused by acquired or hereditary metabolic diseases (metabolic disorders of carbohydrates, fats, nucleoproteins, minerals). Among local factors  there are secretion disorder, secretion congestion, inflammation. Depending on localization and form of organ in which stones appear there are solitary, multiple, round, oval stones, stones with processes, cylindrical, smooth and shaggy stones.  Cholelithic disease and urolithiasis, pressure bedsore, perforation of organs, fistulas, inflammation of walls of caval organs, jaundice, hydronephrosis are the consequences of stone formation.

 Cells and tissues damage and death. Necrosis and apoptosis.  Pathologic anatomy of organ deficiency. Fundamentals of  thanatology.

Death, definition, signs of death

Critical alteration of specialized cells. Definition, etiology and consequences. 

Molecular mechanisms of cells critical alteration. Concepts of  endogenous metabolic catastrophe: cells biological combustion insufficiency, cell  acidotic alteration, plasma membrane transportaion mechanisms injury, activation of cytoplasm lipid peroxidation and cell membranes, injury with free radicals and  nitrogen oxide excess, catastrophic increase of free calcium in cell, cell injury with transmitters excess,  abnormal proteins accumulation in cell. Critical injury of cell with external factors:  external physics–chemical factors, pathogenic infects (ultramicrobs,  Rickettsias, bacteria, fungi).

Kinds of specialized cells death in organism.

Cell necrosis: definition, terms and phases of development, morphologic characteristic of  coagulation necrosis and cells necrosis, their consequences.

Pathogenic inductive apoptosis: definition, molecular mechanisms, term of development,  microscopic manifestation, consequences. 

Immune destruction of cells. Immune destruction of cells in organism conditions and designation.  Phagocytosis: definition, main cells-phagocytes, phagocytosis mechanisms and microscopic manifestation.  Immune cells killing: definition, cytotoxical cells,  mechanisms and microscopic manifestations, consequences. Cells destruction with activated complement: definition, mechanisms and microscopic manifestations.  

Pathological anatomy of organ insufficiency.

        Autoimmune (lymphocytic) destruction of all specialized structures of organ: definition, stages of development,  clinical-morphological characteristics, consequences. 

        Postishemic–markfusional organs injury: definitions, morphogenesis peculiarities,  clinical-morphologic characteristics, consequences.    

Necrosis of organ or its portion.  Morphologic types of tissues necrosis (colliquative,  coagulative): definition, causes, pathological anatomy. Orgaecrosis: definition, causes, development stages (ore-necrotic,  necrosis and tissues destruction). Post necrotic transformation of organ’s  sphacelus  (necrosis demarcation and encapsulation, regeneration,  infection and inflammation,  formation of ulcer, cyst,  sequester,  sclerosis/gliosis foci,  calcinosis foci).

Clinical–morphological classification of orgaecrosis basic kinds. 

Infarction: definition, morphogenesis, pathological anatomy of main types, consequences.  Gangrene: definition, morphogenesis, pathological anatomy of dry, wet and anaerobic, consequences.  Morphologic characteristics of infarction, gangrene. Decubitus: definition, trophoneurotic necrosis morphogenesis,  consequences. Noma: definition, morphogenesis, pathological anatomy, consequences.  Morphogenesis, pathological anatomy of liver toxic necrosis and  enzymatic pancreatonecrosis.  Sequester: definition, morphogenesis, pathological anatomy, consequences.

        Fundamentals of thanatology.

Human being birth and death.  Organism death from biological, social and medical positions: idea of natural, violent death and death from diseases  (untimely and sudden). Intrauterine death definition. 

Thanatogenesis. Cause, molecular–metabolic and structural mechanisms of vital parts activity cessation under natural course of disease. Immidiate consequences of heart, lungs, cerebrum, kidneys and liver work cessation. 

Clinical–pathological characteristics of the main periods of thanatogenesis. Modern acknowledged periods of thanatogenesis: critical period, apparent death, post reanimation period, natural death.  Consequences of vital parts activity cessation. 

Critical and agonal periods of disease: definition, clinical-pathological features, consequences.  

Clinical death: definition, features and terms of development, idea of cardiopulmonary reanimation and its consequences.  

Post reanimation period: definition, molecular and clinical–pathological anatomy features of vital parts injury and their functions recovery.

Natural death: definition, immediate (main) causes and development terms under natural clinical course and under sudden death of a person. Precursory and delayed signs of natural death and resuscitated patient.  Morphological characteristic of cadaveric changes. Basic reasons and morphological signs of  intrauterine fetal death and neonate death. 

       

Critical alteration of specialized cells  is manifested with their death being the final result of their damage. The most often cell’s death is caused by  acute hypoxia or ischemia; physical factors  (mechanical trauma,  burns,  frostbites, radiation, electric shock); chemical substances and medicines; infections, intoxications, immune reactions and other conditions. 

Mechanisms of cells damage

 Mechanisms of cells damage are extremely various.  Under ischemia damage develops in the result of oxygen scarcity in tissues and its  free radicals creation causing  lipids peroxidation and cellular breakdown. Critical damage can develop under calcium homeostasis disturbance.  Under cytolemma hyperpermeability free calcium ions concentration grows causing activation of  numerous ferments’ damaging cell: phospholipase, protease,  ATPase,  endonuclease.  ATP content decrease causes cytolemmas damage and induces cell death.  

Types of specialized cells death.

Three basic types of specialized cells death in organism are recognized: ischemic or hypoxic, toxic and damage with oxygen free radicals. Hypoxic and ischemic damage occurs in the result of  arterial flow cessation. Herewith oxidative phosphorilation is ceased and ATP formation is terminated,  anaerobic glycolysis enhances, lactic acid, inorganic phosphate accumulates,  intracellular pH decreases, chromatin consenses,  cell becomes dropsical, membrane structures destruct. Cell damage by free radicals is caused by  membranes lipids peroxidation,  autocatalytic reactions development, oxic proteopepsis, DNA damage. Toxic damage occurs under chemical substances action on cell membrane or intracellular organelles. 

Two types of local death exists: necrosis and apoptosis.  Necrosis (from Greek nekros – dead) which is local death, death is characterized with cells death in living body. Specific cells, a group of cells, the portion of the organ, organ in full can be subject to death. 

Cells necrosis

 Cell necrosis is cell death under the influence of extreme negative exogenic and endogenic factors and it is manifested with considerable cells edema or cellular breakdown,  cytoplasmic proteins denaturation and coagulation, cell organelles breakdown.  Three stages are differentiated iecrosis development:  pre-necrotic, necrotic and post necrotic. Pre-necrotic stage is characterized with  severe degenerative changed which are ended with necrosis. At necrosis stage the following is broken-down and decomposed (kariorrhexis,  kariolysis), cellular cytoplasm (plasmorrhexis, plasmolysis) and intercellular substance – fibrinoid necrosis.

In the post necrotic stage necrosis products are subject to  autolysis, meaning  dilation or dispersion or organization.  Macroscopically necrosis region differs from surrounding  living tissues.  Its of dirty black color in skin and bowels and whitish yellow in the other organs (myocardium, liver, kidneys,  spleen).

By etio–pathogenetic principle the following direct necrosis is differentiated: traumatic, toxic and the following indirect ones: trophoneurotic, allergic, vascular. 

Microscopic signs of necrosis:

Cell nucleus change:  karyopyknosis, karyorrhexis, kariolysis.

Cell cytoplasm chang: plasma coagulation, plasmorrhesis, plasmolysis.

Intracellular substance change: mucoid swelling, fibrinoid swelling, fibers disintegration.

Necrosis classification by etiology: trophoneurotic, toxic, traumatic, vascular, allergic.

 Trophoneurotic necrosis   occurs under central nervous system and peripheral nerves injury.  Traumatic necrosis  occurs in the result of physical, electrical, chemical, thermal trauma direct action.  Toxic necrosis  occurs in the result of toxins, mostly of bacterial origin influence on tissues.  Allergic necrosis develops on condition of tissues hypersensitivity (sensibilization).  Vascular (ischemic) necrosis occurs in the result of tissues blood supply significant decrease or termination.  

        Clinicopathologic classification of the main types of organs’ and tissues’ necrosis 

        The following types of necrosis are differentiated: coagulation, colliquative, infarction, gangrene,  decubitus, sequester.  

        Coagulation (dry) necrosis is characterized with  sphacelus portion deaquation and induration.  It includes cheesy (caseation) necrosis under  tuberculosis, lues, lymphogranulomatosis as well as  cereous myonecrosis under  abdominal and flea-borne typhus,  cholera,  fibrinoid necrosis under allergic and  lymphocytic diseases,  malignant hypertension as well as  adiponecrosis which is distributed into ferment, which occurs under  pancreatitis and non-ferment caused by trauma. 

Colliquative (wet) necrosis is characterized with necrotic tissue rarefication and fusion  in the result of hydrolytic processes activation.  It is developed in tissues rich with moisture, for example in cerebrum.

Infarction is necrosis caused by blood supply deficiency. Occurs in the result of thrombosis, embolism, long term arteriostenosis and long term, functional overexertion of organ in hypoxia conditions. By its shape infarction could be wedge-like (spleen, lung, kidneys)  and irregular shape (heart, cerebrum). By its appearance it is distributed into white (ischemic), which the most often is found in cerebrum, spleen; red  (hemorrhagic) which occurs in lungs, bowel,  amphiblestrodes; white with hemorrhagic crown  – in heart, kidneys. Infarction form and appearance depends on the features of organ’s vascular system, types of vessels branching, anastomosis development,  structural–functional features of the organ (for detail see the theme of circulatory disturbances).

Gangrene is death of tissues contacting with air (bowel, extremities). Under the influence of air ferric sulphide is formed from hemoglobin, and this ferric sulphide colors necrotic portion in black. Dry and wet gangrenes are differentiated.  Dry occurs mostly in the result of insufficient arterial blood supply. Necrotic portion dries up, densifies, mummifies. Wet gangrene  occurs in the cases when lymph and black blood outflow is disrupted or  when necrosis portion is subject to putrefactive mycronychia action. Necrotic portion is hydropic, diluted, of dirty black color with very unpleasant smell.  Anaerobic gangrene development is based also on blood outflow disrupted. It is caused by a group of anaerobic activators. During that gases squeeze microvasculature structures.

Decubitus is a kind of gangrene. It is caused by blood supply and nervous trophism disturbance of subiculum in the place of squeezing  (sacral bone, bladebones, calx) under seriously ill patient long term decubitus, for example, cerebrovascular accident.

Sequestrum is sphacelus which is not subject for autolysis for a long time. As a rule sequestra are observed in bones under osteomyelitis.

Demarcation line of red color with a tinge of yellow occurs surrounding necrotic portion.  This is reactive inflammation characterized with vascular distention in living tissue, edema,  leukocytic infiltration, macrophages  incipiency.  Lytic ferments of heterophilic leukocytes  expedite dead zymolyte maceration and resolution similar to the one observed under wet necrosis, for example in cerebrum  with cisterns formation and cyst buildup or rejection  (autoamputation) of  external necrotic body parts. In favorable cases mesenhymal origin cells proliferation starts around necrotic portion, spacelous aggregate either grow with conjunctive tissue  (organization) or encrust with it  (encapsulation) or are subject to  calcification (petrification). Sometimes necrotic portion purulence is observed with abscess formation.

Apoptosis

Apoptosis is genetically programmed death of unnecessary or defective cells in living body and  the following causes these cells destruction in the process of  embryogenesis and physiologic involution: cutaneous epithelium, white and red corpuscles   extinction. Herewith chromatin condensation and fragmentation in cells is observed. In case apoptosis decrease neoplastic process is developed and in case apoptosis increase – atrophy. Apoptosis differs from necrosis in:

– inflammation absence,

– only several cells or their groups are involved in the process,

– cell membrane is saved,

– cellular breakdown is done not by activated  hydrolytic ferments, but in participation of special  calcium-magnesium dependent  endonucleases which cut nucleus into numerous fragments,

– formed cells fragments  (apoptosis corpuscles) phagocytized by parenchymatous or stromal cells which are situated nearby.

Apoptosis morphogenesis develops in several stages:

– chromatin condensation and margination, nucleus becomes fragmented,

– intracellular organelles condensation and  cells shrinkage,

– apoptosis corpuscles formation,

– apoptosis corpuscles phagocytosis with  parenchymatous cells or macrophages .

Under histological investigation apoptosis cells are round or oval particles with intensively colored cytoplasm and  dark fragments of nucleus chromatin. 

Fundamentals of thanatology

 Thanatology is doctrine of organism dying starting from  initial signs up to full corruption of the body. In the course of dying organism stays in terminal (critical) condition and is capable for reversible development occur prior to death coming. Herewith progressive functions decrement of various organism’s systems is observed, first of all  respiratory depression as well as blood flow organs depression occurs, organism’s homeostatic systems incoordination has place: pulmonary edema,  arrhythmia,  paroxysm,  respiration disturbance, constrictors paralyses, etc. Hypoxia and blood circulation disturbance  cause pathologic changes in organs and tissues, which are called moribund state.  Blood circulation directed to support functions of cerebrum causes microcirculation disturbance on periphery resulting in  parenhymal organs structure and functions failure. Energy metabolism switches to  anaerobic glycolysis causing  lactic acid accumulation,  acidosis, hypoxia intensifies.  Biologically active substances come into blood causing microcirculation channel paresis and paralysis, increase of vascular permeability, blood clotting, stasis occurrence,  clots formation. Terminal condition  development and signs depend on pathological process caused death agony. In case dying is going on, terminal condition can be divided into several stages: pre-agony, terminal pause, agony,  apparent death, natural death.  During pre-agony stage arterial tension gradually decreases,  inhibition of sensorium and electric activity of cerebrum. Tachycardia passes into  bradycardia, trunkal reflex disturbance occur. In terminal phase temporary breath holding is observed,  and periodic asystolia changes bradycardia.  Agony is characterized with sudden activation of bulbar centers  on the background of cerebral cortex full shutdown. Such disintegration of vegetal centers is accompanied with temporary and short time  arterial tension increase, sinus automatism initiation and   respiratory movements intensification.  Apparent death is characterized with the deepest inhibition of central nervous system which expands also on spinal bulb with blood circulation termination and apnea.  

Death, types, signs,  postmortem changes 

        Depending on the causes the following types of death are recognized:  natural   (physiologic) death from age and organism depreciation, violent death from trauma or other negative influence on organism which ends with death and  from diseases. Depending on reversible or irreversible changes in organism apparent death and natural death are specified.     Apparent death is characterized with apnea, blood circulation termination and lasts for 5-6 minutes until cerebral cells death. Apparent death is reversible process of dying. Reversibility depends on the stage of hypoxic changes in cerebrum. Natural death is manifested with irreversible changes development and  autolytic processes beginning in all the organs.  It has characteristic signs and postmortem changes in tissues: dead body cooling,  postmortem rigidity,  mummification, blood relocation,  postmortem lividity,  cadaveric disintegration. In case death process in fast, it is observed  liquid blood in the heart and vessels caused by fibrinolysis,  postmortem face lividity,  ecchymosis in conjunctiva,  intensive and wide spread cadaveric lividity,  urine, fecal matter discharge as well as  red mucus presence in respiratory passages, considerable venous plethora of internal organs, hemicardia engorgement,     punctuate hemorrhage on heart, lungs surface. 

In case agony comes prior to death  dense blood clots are observed in the heart and vessels  – red in case of short term agony and yellowish-white or white under long term agony.  Following basic vital functions of organism termination, early and late signs of natural death gradually develop in organism.  Early signs are as follows: cadaveric lividity (occur in  30 –60 minutes post mortem), cadaveric rigidity  (occurs in 2-4 hours), cooling  (every hour of death   gives 1 degree dead body temperature decrease, desiccation of specific parts of skin and  mucous coats (the most clearly it can be seen on opened eye sclera  –  Lyarshe spots) and autolysis. Late signs of natural death occur on  2-3 day port mortem. They are  ruining  (putrefaction, dead body damage by plants, animals) and preserving  (grave wax,  mummification,  turfy tannage, etc.). Putrefaction occurs with microorganisms participation and is characterized with  dead body organic substances destruction.  This is accompanied with gases formation, tissues mollities and dilution. First signs of putrefaction occur in large bowel in 24-36 hours, abdominal wall derma turns green because of  sulfgemoglobin accumulation. 

Autopsy.

Autopsy procedure and methods in medical and preventive treatment facilities

Dead body stays in the ward for two hours after the fact of natural death is established by in-patient hospital’s physician. Surname, name, father’s name, date and time of death, department are to be written on the hip with brilliant green. Usually rubber-coated label on which above mentioned passport data is written is fixed to the arm. The latter method is better to use in those medical and preventive treatment facilities in which sporadic death cases occur. 

Under body lift and its further examination it’s necessary to keep all moral-ethical and professional requirements.  Ethical requirements include medical secrecy keeping regarding everything revealed at autopsy (thanatopsy).  It’s also should be taken in mind that dead body serving for science has relatives and family.   For example, Professor V.Gruberg required from students and those working in autopsy room to  take off hats, as “hats wearing does not correspond the credit of the room“. It’s advised to warn junior health professionals of the fact that cadaveric hypostasis can disfeature the face in case body stays dorsum upwards.  It should be kept in mind that after natural death fact is etsbalished it’s necessary to close eyes,  fasten up lower jaw, to cover the body with clean  linen, etc. Simultaneously with diseased body completely filled-in medical records should be submitted to mortuary. 

Prior to deceased body autopsy anatomist studies all the data regarding patient’s life, disease and death which can be found in medical card of hospital patient,  asks attending doctor missed facts relating to  course of disease and dying. Sometimes it’s useful to clarify some data from relatives, especially in case patient’s short term stay in the hospital.  The following should be carefully investigated:  laboratory, tolls and other methods of investigations, methods of treatment, medicines potions taken by patient, diagnosis written on title page of medical records as well as all working diagnosis written in log books. All this circumstances study pursues one more important aim – to exclude or to find out  medicolegal aspect. 

It’s desirable that anatomist examining all necessary data independently formulated diagnosis which can differ of attending doctor diagnosis. Doing this, as P.Kalitiyevskyi mentions, anatomist in a certain manner  puts her/himself in the position of  attending doctor, which is really important for mutual understanding between anatomist and clinician. 

There is certain algorithm in autopsy fulfillment:

1 To carry out autopsy in day light as artificial lighting changes color transfer. 

2 To put on gown and rubberized apron and oversleeves.  It’s advisable to use anatomical gloves. This will ensure contagious diseases prevention, as well as cadaveric alkaloid penetration through possible defects of skin. 

3 External examination of diseased body.  The following should be established: sex, body-type, nutrition,  state of integumentum,  existence of death signs,  eruptions,  hematomas, wounds, ulcerations, edema, etc. It’s desirable that attending doctor could confirm passport data of diseased. 

4 Main incision. It’s necessary to watch to prevent it coming through after surgical sections,  cicatrix and other defects. 

5 Detailed examination of cavities establishing the position and interlocation of organs, presence of  joints,  exudates, transudate, foreign objects, etc. 

6 Organs’ withdrawal from the cavities and their investigations (size, weight, color, consistency,  shape, etc.) with simultaneous necropsy taking and, depending on tasks set for anatomist, material for bacteriologic,  serologic, biochemical and virology investigations. Sometimes X–ray examination of bones is done. 

7 Short summary incorporating paragnosis, the cause of death, possible discrepancies between clinical diagnosis and paragnosis, accessory matters clarification which are of interest for clinicians. 

8 Cadaver toilette.

9 Autopsy records keeping.

First autopsy methods were described in details by  R.Virhov. Later on it was improved by  Kiary, L’Etule, O.Abrykosov, G.Shore.  methods of two last ones are the most widely used in anatomists’ practice. 

O.Abrikosov offers to investigate organs by cavities. First organs of cervix and thoracic cavity are removed   in totality. Then separately intestinal tract, liver, stomach and dodecadactylon in one set, urinary tracts and genital organs in totality. 

G.Shore suggested organs full evisceration method, which means removal of  cervix, thoracic cavity, abdominal cavity and small pelvis as single total complex. This method is rather convenient to be used under investigation of those deceased bodies who died of after surgery complications. In this cases it’s reasonable to search in details field of operation area, namely  state of surgical sutures, vessels, exudates presence and character, correctness of surgery fulfillment. 

Autopsy recording

Autopsy recoding should be done in autopsy document – records of post mortem examination (autopsy). It consists of the following parts:  passport, descriptive,  paragnosis and clinical autopsy epicrisis.  Passport portion includes data regarding deceased’ surname, name and father’s name, his/her age, address, number of in-patent’s observation records,  profession and specialty,  the date of admission to the hospital and date of death, diagnosis.  Autopsy records should contain also brief extract from observation records regarding features of etiology,  clinical implications,  tools and laboratory results, methods of treatment.  Take into consideration that it’s advisable to indicate specialty instead of writing “retired”, as well as characteristic features of disease which made it possible to   make diagnosis mentioned in clinics. 

There are various procedures to fill-in descriptive part.  At present there is a tendency to simplify it, to go apart from classical form of presentation.  It’s unacceptable to use general terms, for example  “atherosclerosis“, “adenoma“, “pneumosclerosis“, etc. instead of pathologic signs or to compare the size of pathologic changes with such objects as  English walnut, pea, egg instead of accurate statement of dimensions. It should be remembered that autopsy records is legal document in which minor changes, which, to the opinion of anatomist, are not critical could be of first priority under further examination.   Moreover it’s not feasible to use autopsy records in which  the character of pathologic changes is only emphasized. This way often causes mistakes, which are hard to correct. Making pictures and audio tape recording are also considered to be ancillary methods of recording. The basic requirement imposed to descriptive part of records is sufficient completeness and  distinctness combined in case possible with briefness of presentation. 

The following forms of pathologicoanatomic changes registration are widely used in autopsy practice:

Ø   by anatomic systems of organism;

Ø   by the way of autopsy fulfillment;

Ø   by preliminary defined place of system injury in conformance with peculiarities of the case,  and further on  – by the way of other systems examination. 

It’s always recommended to start descriptive part from body appearance description, registration of nutrition, status of skin integuments, mucus tunic, eyes, hair, nails, character of edema, etc.  These features are sometimes sufficient to assume this or that pathology presence.  It’s advisable to make records immediately following autopsy  and do not defer that on the next day,  it’s better to make records at dictation by stages of autopsy carrying out or using  voice recorder. 

Pathologoanatomic diagnosis formulation follows descriptive part of records, based on  macroscopic diagnostics and in case necessary using express-methods. Diagnosis formulation is advised to be done in attending doctors presence prior to the body toilette. 

Pathologicoanatomic diagnosis structure and composition

 Diagnosis is medical conclusion regarding pathologic state of health of the person under examination, presence of disease (trauma)  or the cause of death expressed in terms, provided by International classification of diseases, traumas and causes of death.   Making diagnosis is the final stage of the data of anamnesis, clinics, laboratory–tools investigations, macro- and microscopic morphology examination results analysis. 

The following variants of diagnostic process are differentiated depending to its stages:

Ø   diagnosis under long term health condition observation by territory or family  physicians, and prophylaxis observations  

Ø   diagnosis at admission to  medical-diagnostic establishment;

Ø   clinical diagnosis by which treatment is carried out; This is final clinical diagnosis which is to be made by attending doctor  at patient’s release from the hospital or in case of death;

Ø   pathologoanatomical (legal) diagnosis made by anatomist  (medical examiner) based on sectional and biopsy material examination .

Up–to–date clinical and pathologoanatomic diagnosis should represent  nosology, etiology, pathogenesis,  morphofunctional manifestations and prognosis of disease. That is to say pathologoanatomic diagnosis should include all the stages of cognitive process:  observation, morphofunctional characteristic of pathologic changes,  disease nosology attribute definition (formal diagnosis), describe etiology, interrelationship and sequence of morphologic manifestations occurrence taking into consideration data of  anamnesis, clinical signs and  complex of laboratory-tools and morphologic intravital analysis results   (clinical diagnosis of this patient or deceased), as well as prognosis in case diagnosis making based on biopsy examination. 

It should be kept in mind that each nosology unit contains the reason as well as probable consequence which realize in certain conditions only. Cause and effect are interconnected with  possibility and reality, contingency and probability. At this connection between the cause and contingency incorporates  consequence variability on the same cause and possibility of cause transfer into effect is defined by probability. 

Under pathologoanatomical diagnosis making it’s necessary to take into consideration as follows: 

Ø   one reason can cause one consequence;

Ø   one reason can cause a number of consequences;

Ø   one consequence can be caused by a number of reasons;

Ø   patient’s death can be caused by reason and consequence (consequences);

Ø   reason and consequence (consequences) can change disease manifestations   (pathomorphism).

        It’s often that attending doctors and anatomists interpret and understand the same phenomena in a different way, as well as their place among the other  processes found at patient  from the point of view of cause and effect,  their significance in the course of disease, as well as of diagnostic positions.  Clinicians often establish as basic nosology unit manifestation of disease or complication on which their curative or reanimation actions were directed. This is the ground to understand that without unified principles of pathologic anatomy processes interpretation and registration collaboration of attending doctors and prosectors will be inefficient and will not be useful for clinical practice and doctor’s skills improvement which should be its result. 

Final diagnosis is the result of complicated process of numerous facts comparison and apprehension, collected by doctor in the process of treatment which is based on formal and dialectical logic’s laws. Diagnosis defining is not formal stage, but the conclusion of doctor’s mentation expressed in written form.  In such a way there should be accurate principles of its expression understandable for attending doctor, prosector as well as comprehensible under statistic analysis of population death rate. 

Clinical analysis and paragnosis consist of    divisions

1 Principal diseases.

2 Principal disease complications.

3 Concurrent diseases.

Principal disease should be nosologic form which by itself or through pathogenically connected complications caused   functional diseases lead to patient’s clinical picture and afflicted death.  For example,  peptic ulcer diseases,  lung cancer,  croupous pneumonia,  rheumatism, etc. Herewith it’s not feasible to list symptoms and syndromes to substitute nosologic unit. 

Clinical–pathology anatomical epicrisis    is the most complicated autopsy records division to be formulated.  This is synthesis of the clinical course of disease and the data found under  morphologic examination, determination of etiology, morphogenesis and mechanism of death.  Prosector states in it his/her view on the features of this specific case. 

        Clinical–pathology anatomical epicrisis    should cover the following matters: 

1 Substantiation of diagnosis:  principal disease, complications, concurrent disease. 

2 Clarification of  thanatogenesis links and primary and immediate causes of death establishment;

3  Pathomorphism manifestations analysis  (medical actions influence on disease clinical-morphological manifestations);

4 Diagnosis comparison by headings  (principal disease,  its complications and concurrent diseases) mentioning the cause of  diagnosis discrepancy;

5 Clarification of diagnostics and patient’s admission expediency evaluating this factor influence on  curative process and disease consequence.

There is not any distinct scheme of clinical-pathological anatomy epicrisis which is caused by the fact that specific approach is possible for every specific case. In the other words, this is subjective prosector’s view on     disease with morphological analysis utilization.  However, taking into consideration that major part of it content is devoted to clinical picture and  treatment analysis, possibilities of  early pre-hospital and hospital diagnosis, necessary diagnostic measures use, timely patient’s admission, diagnostic process dynamics,  surgery feasibility, characteristic of  therapy,   reanimation measures,  these principal matters are advisable to be peer reviewed, under attending doctors active participation,  during medical session,  clinical-pathology anatomical conference. Only in such a way it’s possible to express medical cogitation errors and failures of treatment-prophylaxis work in every specific case. 

Pathologic Calcification 

Pathologic calcification is the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts. It is a common process occurring in a variety of pathologic conditions. There are two forms of pathologic calcification. When the deposition occurs locally in dying tissues, it is known as dystrophic calcification; it occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism. In contrast, the deposition of calcium salts in otherwise normal tissues is known as metastatic calcification, and it almost always results from hypercalcemia secondary to some disturbance in calcium metabolism. 

DYSTROPHIC CALCIFICATION

Dystrophic calcification is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat. Calcification is almost inevitable in the atheromas of advanced atherosclerosis. It also commonly develops in aging or damaged heart valves, further hampering their function. Whatever the site of deposition, the calcium salts appear macroscopically as fine, white granules or clumps, often felt as gritty deposits. Sometimes a tuberculous lymph node is virtually converted to stone. 

Morphology. Histologically, with the usual hematoxylin and eosin stain, the calcium salts have a basophilic, amorphous granular, sometimes clumped, appearance. They can be intracellular, extracellular, or in both locations. In the course of time, heterotopic bone may be formed in the focus of calcification. On occasion, single necrotic cells may constitute seed crystals that become encrusted by the mineral deposits. The progressive acquisition of outer layers may create lamellated configurations, called psammoma bodies because of their resemblance to grains of sand. Some types of papillary cancers (e.g., thyroid) are apt to develop psammoma bodies. Strange concretions emerge when calcium iron salts gather about long slender spicules of asbestos in the lung, creating exotic, beaded dumbbell forms.

Pathogenesis. In the pathogenesis of dystrophic calcification, the final common pathway is the formation of crystalline calcium phosphate mineral in the form of an apatite similar to the hydroxyapatite of bone. The process has two major phases: initiation (or nucleation) and propagation; both can occur intracellularly and extracellularly. Initiation of intracellular calcification occurs in the mitochondria of dead or dying cells that accumulate calcium. Initiators of extracellular dystrophic calcification include phospholipids found in membrane-bound vesicles about 200 nm in diameter; in cartilage and bone, they are known as matrix vesicles, and in pathologic calcification, they are derived from degenerating or aging cells. It is thought that calcium is concentrated in these vesicles by a process of membrane-facilitated calcification, which has several steps: (1) calcium ion binds to the phospholipids present in the vesicle membrane, (2) phosphatases associated with the membrane generate phosphate groups, which bind to the calcium, (3) the cycle of calcium and phosphate binding is repeated, raising the local concentrations and producing a deposit near the membrane, and (4) a structural change occurs in the arrangement of calcium and phosphate groups, generating a microcrystal, which can then propagate and perforate the membrane. Propagation of crystal formation depends on the concentration of Ca2+ and PO4 and the presence of inhibitors and other proteins in the extracellular space, such as the connective tissue matrix proteins. 

Although dystrophic calcification may be simply a telltale sign of previous cell injury, it is often a cause of organ dysfunction. Such is the case in calcific valvular disease and atherosclerosis, as becomes clear in further discussion of these diseases. 

METASTATIC CALCIFICATION

Metastatic calcification may occur iormal tissues whenever there is hypercalcemia. Hypercalcemia also accentuates dystrophic calcification. There are four principal causes of hypercalcemia: (1) increased secretion of parathyroid hormone (PTH) with subsequent bone resorption, as in hyperparathyroidism due to parathyroid tumors, and ectopic secretion of PTH-related protein by malignant tumors; (2) destruction of bone tissue, occurring with primary tumors of bone marrow (e.g., multiple myeloma, leukemia) or diffuse skeletal metastasis (e.g., breast cancer), accelerated bone turnover (e.g., Paget disease), or immobilization; (3) vitamin D-related disorders, including vitamin D intoxication, sarcoidosis (in which macrophages activate a vitamin D precursor), and idiopathic hypercalcemia of infancy (Williams syndrome), characterized by abnormal sensitivity to vitamin D; and (4) renal failure, which causes retention of phosphate, leading to secondary hyperparathyroidism. Less common causes include aluminum intoxication, which occurs in patients on chronic renal dialysis, and milk-alkali syndrome, which is due to excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate. 

Metastatic calcification may occur widely throughout the body but principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins. Although quite different in location, all of these tissues lose acid and therefore have an internal alkaline compartment that predisposes them to metastatic calcification. In all these sites, the calcium salts morphologically resemble those described in dystrophic calcification. Thus, they may occur as noncrystalline amorphous deposits or, at other times, as hydroxyapatite crystals. 

Usually, the mineral salts cause no clinical dysfunction, but, on occasion, massive involvement of the lungs produces remarkable x-ray films and respiratory deficits. Massive deposits in the kidney (nephrocalcinosis) may in time cause renal damage