Pathomorhology

4,811 views
4,605 views

Published on

0 Comments
11 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
4,811
On SlideShare
0
From Embeds
0
Number of Embeds
4
Actions
Shares
0
Downloads
159
Comments
0
Likes
11
Embeds 0
No embeds

No notes for slide

Pathomorhology

  1. 1. 1 CRIMEAN STATE MEDICAL UNIVERSITY NAMED AFTER S.I.GEORGIEVSKY Digest on pathomorphology Professor ALEXANDR ZAGOROULKO Assistant of professor TATYANA FILONENKO Crimea, Simferopol 2007
  2. 2. 2 УДК 616-091 Z 16 Рецензенти І.В.Задніпряний – д.м.н., професор кафедри анатомии КДМУ ім. С.І.Георгієвского О.Ю.Шаповалова – д.м.н., профессор, завідувач кафедри гістології КДМУ ім. С.І. Георгієвского Друкується в авторскій редакції. О.Загорулько, Т.Філоненко «Дайджест з патоморфології». – Сімферополь, 2007.-417с. – Мова англ. ISBN 966-73348-14-8 «Дайджест з патоморфології» (друге видання) підготовлений Академіком Міжнародної Академії Патології, завідувачем кафедри патоморфології Кримського державного медичного університету Олександром Загорулько і доцентом кафедри Тетяною Філоненко. Книга містить короткий огляд головних тем з загальної і клінічної патоморфології відповідно до програми, затвердженої Центральним методичним кабінетом вищої освіти Міністерства охорони здоров’я України. Книга розрахована на студентів медичних вузів, які навчаються англійською мовою. Z 143 Z 143 A.Zagorоulko, T.Filonenko «Digest on pathomorphology». – Simferopol, 2007. – 417 p. ISBN 966-73348-14-8 “Digest on pathomorphology” (second edition) is prepared by Academician of International Academy of Pathology, Head of the Department of Pathology of the Ctimean State Medical University, professor Alexander Zagoroulko, PhD, MD and assistant of professor Tatyana Filonenko, PhD. The book includes the quick review of the main topics on general and systemic pathomorphology. All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner.
  3. 3. 3 Preface In the preface to the first edition we stated our motive as follows: “We believe that communication by verbal and written methods are fundamental basis for study and lerning. Nevertheless, in the mordern setting where knowledge increases so rapidly and in subject such as pathology where morphological changes are a major component, we consider that the quick review has an important facilitating role”. The first edition of the present book is abridged information about the main topics of the pathomorphology, which combined the efforts of the scientific achievements of the all pathomorphologists as in theUkraine and other countries as well. We have attempted to extract the essential elements from the various pathomorphological literatures for facilitation of the understanding of pathomorphology. Because pathology is the basis of our medical practice, or, in the words of Sir William Osler, “As is our pathology, so is our practice.” This book is expected to fulfil the following goal: as an aid to students to revise the subject quickly near the examinations in short period of time.
  4. 4. 4 PART I. GENERAL PATHOLOGY INTRODUCTION ON PATHOLOGY Pathology is scientific study of structure and function of the body in disease. The discipline of pathology forms a vital bridge between initial learning phase of preclinical sciences and the final phase of clinical subjects. PATHOLOGY is the study (logos) of suffering (pathos). It is a discipline involving both basic science and clinical practice and is devoted to the study of the structural and functional changes in the cells, tissues, and organs that underlie “diseases”. Pathology studies (1) cause of the disease (etiology), (2) the mechanisms of its development (pathogenesis), (3) the structural alterations induced in the cells, organs and tissues of the body (morphological changes), and (4) the functional consequences of the morphologic changes (clinical significance). CELLULAR INJURY AND CELLULAR DEATH Etiology of cellular injury The causes of cellular injury, reversible or irreversible, may be broadly classified into two large groups: 1. Genetic causes. 2. Acquired causes. The acquired causes of disease comprise the vast majority of common diseases and can be further categorised as the follows: 1. Hypoxia and ischemia. 2. Physical agents (mechanical trauma, thermal trauma, ultraviolet and ionizing radiation, rapid changes in atmospheric pressure). 3. Chemical agents and drugs. 4. Infectious agents. 5. Immunologic agents. 6. Nutritional derangements. 7. Physiologic factors. Acute Cell Injury Reversible cellular injury is characterized with the ability of the cell to return to its normal state after withdrawal of an acute stress. Reversible injury is manifested with hydropic swelling of the cell (cellular edema), dilation of endoplasmic reticulum, and detachment of ribosomes from the granular endoplasmic reticulum, dissociation of polysomes into monosomes, mitochondria swelling and enlargement, blebs of plasma membrane, nucleolar alterations with disaggregation of granular and fibrilar elements. Irreversible cellular injury or cellular death is necrosis and apoptosis. Morphogenetic mechanisms of intra- and extracellular accumulations Mechanisms of the development of intra- and extracellular (stromal) degenerations (dystrophies) are the followings: 1. Infiltration – redundant accumulation (deposition) of metabolites into the cells and extracellular matrix. 2. Decomposition (phanerosis) – disintegration of membranous structures of the cells and extracellular matrix. 3. Perverted synthesis - synthesis of abnormal substances in the cells and tissues. 4. Transformation – formation of one type of metabolism‟s products from common initial substances for proteins, fats and carbohydrates.
  5. 5. 5 INTRACELLULAR ACCUMULATIONS (PARENCHYMAL DEGENERATIONS OR DYSTROPHIES) Intracellular accumulations are the accumulation of abnormal amounts of various substances in the cells. The stockpiled substances fall into three categories: 1. A normal cellular constituent accumulated in excess, such as water, lipid, protein, and carbohydrates. 2. An abnormal substance such as mineral, or a product of abnormal metabolism. 3. A pigment or an infectious product. Parenchymal degenerations occur in functional cells such as: cells of a liver, kidneys, a myocardium and are characterized by accumulation in their cytoplasm proteins, fats and carbohydrates. It is accompanied by decrease (reduction) of function of enzymic systems and occurrence of structural changes in cells. The most often causes of parenchymal dystrophies are hypoxia, the intoxication, and also enzymopathy - genetically determined diseases at which is observed an inconsistency of enzymic systems in cells. In result enzymopathy there is an accumulation in cells of any products of a metabolism. Such diseases are named as storage diseases. Intracellular proteinous degenerations There are four kinds of intracellular accumulations of proteins: 1. A granular degeneration (dystrophy). Macroscopical kind of organs at this dystrophy it is determined as “muddy or dim swelling”. At a section the organs are dim, swollen. Microscopical descriptions of cells on electronics level: presence of electrondense granules in cytoplasm of the cells. 2. Hyaline-drop degeneration (dystrophy) is characterized by the aggregation of small proteins granules into cytoplasm of cells. It is not determined macroscopically. This dystrophy occurs in kidneys, liver and myocardium. The cytoplasm of plasma cells shows pink hyaline inclusions called Russell's bodies representing synthesised immunoglobulins, the cytoplasm of hepatocytes shows eosinophilic globular deposits of a mutant protein. Mallory's body or alcoholic hyaline in the hepatocytes is intracellular accumulation of intermediate filaments of cytokeratin. The outcome is negative. The focal or total coagulative necrosis develops. 3. Hydropic (cloudy, vacuolar, balloon) degeneration is characterized by accumulation of water within the cell due to cytoplasmic vacuolation. The common causes include bacterial toxins, chemicals, poisons, burns, and high fever. The affected organ such as kidney, liver or heart muscle is enlarged. The cut surface bulges outwards and is slightly opaque. Microscopically: the cells are swollen and the microvasculature compressed. Small clear vacuoles are seen in the cells. These vacuoles represent distended cisternas of the endoplasmic reticulum. Ultrastructural changes in hydropic swelling include the following:  Dilation of endoplasmic reticulum.  Mitochondrial swelling.  Blebs on the plasma membrane.  Loss of fibrillanty of nucleolus. The outcome is negative, because the focal or total colliquative cellular necrosis develops. 4. Keratoid (horney) degeneration is characterized by increase production of keratin substance. This process may be local and general. The intracellular keratin may be located in epidermis of skin, keratinic squamous epithelial cells, cervix, and esophagus. Leucoplakia means hyperkeratosis in mucosa. Leucoplakia may lead to malignization. For example: Squamous cell carcinoma with keratinization. The groups of keratinized cells can be found in the center of squamous cell carcinoma‟s areas. These cell‟s complexes here and there look like rose color homogenous found forms (“canceromatous perls”). Intracellular fatty degenerations Intracellular fatty degenerations are the abnormal accumulations of triglycerides within parenchymal cells. The heart, liver, kidneys are damaged most frequently. The main cause of fatty degeneration is hypoxia, which may be due to: 1. Excess alcohol consumption (most commonly). 2. Chronic cardiovascular and chronic pulmonary insufficiency. 3. Cachexia, avitaminosis. 4. Infections (e.g. diphtheria, tuberculosis). 5. Late period of pregnancy. 6. Starvation.
  6. 6. 6 7. Malnutrition. 8. Hepatotoxins (e. g. carbon tetrachloride, chloroform). 9. Certain drugs (e. g. administration of estrogen, steroids, tetracycline). In the case of cell injury by chronic alcoholism, many factors are implicated with increased lipolysis, increased free fatty acid synthesis, decreased tryglyceride utilisation, decreased fatty acid oxidation to ketone bodies, and block in lipoprotein excretion. An alcoholic who has not developed progressive fibrosis in the form of cirrhosis, the enlarged fatty liver may return to normal if the person becomes teetotaler. Morphological features of fatty change: Fat in the tissue can be demonstrated by frozen section followed by fat stains such as Sudan 3 (red color), oil red O and osmic acid. 1. Fatty degeneration of the liver  Macroscopically the fatty liver is enlarged with rounded margins.  The cut surface bulges slightly and is pale-yellow and is greasy to touch. It is called “goose liver”.  Microscopically: there are numerous lipid vacuoles in the cytoplasm of hepatocytes. The vacuoles are initially small (microvesicular), but with progression of the process, the vacuoles become larger pushing the nucleus to the periphery of the cells (macrovesicular).  At times, the hepatocytes laden with large lipid vacuoles may rupture and lipid vacuoles coalesce to form fatty cysts. Infrequently, lipogranulomas may appear. 2. Fatty degeneration of the heart  It is also called “Tiger’s” heart.  Macroscopically the heart is enlarged, the chambers are stretched, flabby.  Microscopically we can see dust-like fatty vacuoles in the cardiomyocytes.  It is observed in the papillary muscles and trabecules of the ventricles in the form of bands (surrounding the veins). 3. The kidneys look like “large white kidney”. They are enlarged, flabby. The cortical substance is gray with yellow drops. Outcomes of fatty degenerations are seldom reversible. Necrosis or sclerosis may develop. Intracellular carbohydrate degenerations Carbohydrates are divided into 3 groups: 1. Polysaccharides (glycogen). 2. Mucopolysaccharides. 3. Glycoproteides (mucin, mucoid). There are several special reactions for identification of these carbohydrates. Best‟s carmine and PAS (periodic acid-Schiff) staining may be employed to confirm the presence of glycogen in cells. Polysaccharides and mucopolysaccarides are stained dark pink or red. Staining according to Haile for identification glycoproteides. Glycoproteides are stained blue. Accumulations of glycogen     Accumulations of glycogen are excessive intracellular deposits of glycogen usually in patients with an abnormality of either glucose or glycogen metabolism. Morphological features – appearance of glycogen masses as clear vacuoles within the cytoplasm developed with special stain – PAS-reaction. In diabetes mellitus - the prime example of this disorder – the red color granules of glycogen can be found with large magnification in the epithelial cells of Henley‟s loops and in the lumen of kidney‟s canals. Amount of glycogen in the tissues reduces sharply (e.g. in the liver) which causes its fat infiltration (fatty liver degeneration). Mucoid change Mucus secreted by mucous glands is a combination of proteins complexes with mucopolysaccharides Mucin, a glycoprotein, is its main constituent. Mucin is normally produced by epithelial cells of mucous membranes and mucous glands, as well as by some connective tissues like in the umbilical cord. Epithelial mucin is stained positively with periodic acid-Shiff (PAS), while connective tissue mucin does not but is stained positively with colloidal iron. Both are, however, stained by alcian blue. Epithelial mucin is associated with:
  7. 7. 7     Catarrhal inflammation of mucous membrane (e. g. of respiratory tract, alimentary tract, uterus). Obstruction of duct leading to mucocele in the oral cavity, chronic appendicitis and gall bladder. Cystic fibrosis of the pancreas or mucoviscidosis. Mucin-secreting tumors (e. g. of ovary, stomach, large bowel etc.). Storage diseases There are a lot of diseases, which are due to hereditary factors and connected with metabolism disturbance. These diseases are called storage diseases or enzymopathy. A few general comments can be made about all storage diseases:  All the storage diseases occur as a result of autosomal recessive, or sex-(X-) linked recessive genetic transmission.  Most of the storage diseases are lysosomal storage diseases. Out of the glycogen storage diseases, only type II (Pompe‟s disease) is due to lysosomal enzyme deficiency. According to the type of metabolism disturbance storage diseases have been classified into:  Proteinoses  Lipidosis  Glucogenoses The type of proteinoses, lipidosis and glycogenoses depends on the defect in the enzyme. The most frequent lipidosis are Gaucher‟s disease, Niemann-Pick disease. Gaucher’s Disease This is an autosomal recessive disorder in which there is deficiency of lysosomal enzyme, glucocerebrosidase, which normally cleaves glucose from ceramide. This results in lysosomal accumulation of glucocerebroside (ceramide-glucose) in phagocytes of the body and sometimes in the neurons. The main sources of glucocerebroside in phagocytic cells of the body and sometimes in the neurons are the membrane glycolipids of old leukocytes and erythrocytes, while the deposits in the neurons consist of gangliosides. Clinically, there are 3 types of Gaucher’s disease: 1. Type 1 or classic form is the adult form of the disease in which there is storage of glycocerebrosides in the phagocytes of the body, principally involving the spleen, liver, bone marrow and lymph nodes. This is the most common type comprising 80% of all cases of Gaucher‟s disease. 2. Type II is the infantile form in which there is progressive involvement of the central nervous system. 3. Type III is the juvenile form of the disease having features in between type I and type II, i.e. they have systemic involvement like in type I and progressive involvement of the central nervous system (CNS) as in type II. Morphology   In addition to involvement of different organs and systems (splenomegaly, hepatomegaly, lymphadenopathy, bone marrow and cerebral involvement), a few other features include pancytopenia, or thrombocytopenia secondary to hypersplenism, bone pains and pathologic fractures. Microscopically large number of characteristically distended and enlarged macrophages called Gaucher cells which are found in the spleen, liver, bone marrow and lymph nodes, and in the case of neuronal involvement, in the Virchow-Robin space. The cytoplasm of these cells is abundant, granular and fibrillar resembling crumpled tissue paper. They have mostly a single nucleus but occasionally may have two or three nuclei. These cells often show erythrophagocytosis and are rich in acid phosphatase. Niemann-Pick Disease    This is also an autosomal recessive disorder characterized by accumulation of sphingomyelin and cholesterol. Majority of the cases (about 80%) have deficiency of sphingomyelinase, which is required for cleavage of sphingomyelin, while a few cases probably result from deficiency of an activator protein. The condition presents in infancy and is characterized by hepatosplenomegaly, lymphadenopathy and physical and mental underdevelopment.
  8. 8. 8  About a quarter of patients present with familial amaurotic idiocy with characteristic cherry-red spots in the macula of the retina.  The storage of sphingomyelin and cholesterol occurs within the lysosomes, particularly in the cells of mononuclear phagocyte system.  The cells of Niemann-Pick disease are somewhat smaller than Gaucher cells and their cytoplasm is not wrinkled but is instead foamy and vacuolated which stains positively with fat stains.  These cells are located in the spleen, liver, lymph nodes, bone marrow, lungs, intestine and brain. The most frequent glycogen storage diseases or glycogenosis are Pompe’s disease, Mc Ardle’s disease and Gierke disease. There is defective metabolism of glycogen due to genetic disorders. Pompe’s Disease. This is also an autosomal recessive disorder due to deficiency of a lysosomal enzyme, acid mahase. Its deficiency results in accumulation of glycogen in many tissues, most often in the heart and skeletal muscles leading to cardiomegaly and hypotonia. Mc Ardle’s Disease. The condition occurs due to deficiency of muscle phosphorylase resulting in accumulation of glycogen in the muscle (deficiency of liver phosphorylase). The disease is common in 2nd to 4th decades of life and is characterized by painful muscle cramps, especially after exercise, and detection of myoglobinuria in half the cases. Gierke Disease. This condition is inherited as an autosomal recessive disorder due to deficiency of enzyme, glucose-6-phosphatase. In the absence of glucose-6-phosphatase, excess of normal type of glycogen accumulates in the liver and also results in hypoglycemia due to reduced formation of free glucose from glycogen. As results, fat is metabolized for energy requirement leading to hyperlipoproteinemia and ketosis. Other changes due to deranged glucose metabolism are hyperuricemia. The disease manifests clinically in infancy with failure to thrive and stunted growth. Most prominent feature is enormous hepatomegaly with intracytoplasmic and intranuclear glycogen. The kidneys are also enlarged and show intracytoplasmic glycogen in tubular epithelial cells. Other features include gout, skin xanthomas and bleeding tendencies due to platelet dysfunction. The outcome of storage diseases is unfavorable because of insufficienty of the respective organ. EXTRACELLULAR ACCUMULATIONS (MESENCHYMAL DEGENERATIONS) Mescnchymal (stromal vascular) degenerations develop in the connective tissue as a result of metabolic disturbances in it. Stromal vascular proteinous degenerations Proteinous mesenchymal degenerations occur as mucoid swelling, fibrinoid changes, hyalinosis and amyloidosis. The first three types are the stages of connective tissue disorganization. The causes of mucoid swelling, fibrinous changes and hyalinosis are the same as they are the stages of one process. They are immunopathological and autoimmune states, hypoxia, infections. These types of connective tissue disorganization are frequently observed in hypertension, rheumatism and other diseases of the connective tissue accompanied by immune disturbances as well as in allergic diseases, diabetes mellitus, etc. In the majority of cases the arterial walls, heart valves, endocardium, epicardium, articular connective tissue are involved. 1. Mucoid swelling      Mucoid swelling is superficial reversible disorganization of the connective tissue. These processes are associated with swelling of collagen fibers, increased vascular permeability (due to glucosaminoglycans (GAG) action) and plasmorrhagia. Microscopic examination shows metachromasia. Under normal conditions the main substance is basophilic. In this case staining with toluidine blue demonstrates reddish coloring. Macroscopic appearance is absent. The outcome may be reversible. In other cases, the development of fibrinoid swelling is possible. 2. Fibrinoid changes  Fibrinoid swelling is deep irreversible connective tissue disorganization.
  9. 9. 9       Fibrinoid is formed as a result of the main substance destruction and more increase in vascular permeability. The appearance of the organs is changed a little. The main signs are revealed microscopically: the bands of collagen fibers are homogenous, impregnated with plasma proteins. Metachromasia is not marked due to GAG depolymerization of the main substance. Fibrinoid swelling may be generalized (in systemic diseases of the connective tissue) and localized (in chronic inflammations). The outcomes are fibrinoid necrosis, sclerosis or hyalinosis. 3. Hyaline changes (hyalinosis)           Hyaline changes (hyalinosis) - (greek “hyalos” - transparent, glass-like) usually refers to an alteration within cells or in the extracellular matrix, which gives a homogenous, glassy, pink appearance in routine histologic sections stained with hematoxilin and eosin. Hyalinosis develops as a result of plasma infiltration, fibrinoid swelling, inflammation, necrosis, and sclerosis. Hyalinosis is classified according to its localization (vascular hyalinosis and connective tissue hyalinosis) and propagation (generalized and localized). Vascular hyalinosis involves the arterioles and small arteries. In their walls, the endothelium, basement membranes, and smooth muscle cells are damaged. Three types of vascular hyaline are distinguished depending on the pathogenetie character of its formation: 1) simple, 2) lipohyaline, 3) compound hyaline. Microscopic study of the arteries demonstrates thickened walls with sharply narrowed or obliterated lumen. At first, hyaline is accumulated in subendothelial areas of the vascular wall, and then it destroys elastic and middle membranes. In long-standing hypertension and diabetes mellitus, the walls of arterioles, especially in the kidney, become hyalinized, owing to extravasated plasma‟s protein and deposition of basement membrane material. Hyalinosis of connective tissue is usually localized; it develops in scars, adhesions, in the areas of chronic inflammation (e.g. “glazed spleen”). The outcome of hyalinosis is irreversible. Functional significance of hyalin is different. Thus, vascular hyalinosis may lead to atrophy or sclerosis, infarction of organs. Local hyalinosis in the cardiac valves results in heart defects. Amyloidosis Amyloidosis is the term used for a group of diseases characterised by extracellular deposition of fibrillar proteinaceous substance called amyloid. Nature and etiology Amyloid is composed of 2 main types of complex proteins: 1. Fibril proteins comprising about 90% of amyloid. 2. P-component constituting the remaining 10% of amyloid. Fibril Proteins By electron microscopy the major component of amyloid material (about 90%) consists of meshwork of fibril proteins. Chemically 2 major forms of amyloid fibril proteins are identified which have different origins and are seen in distinct clinicopathologic conditions:  AL (amyloid light chain) protein. AL protein of fibrils consists of polypeptides, which may be made up of whole immunoglobulm light chains or fragment of light chains. AL type of fibril protein is produced by immunoglobulin-secreting cells and is, therefore, seen in association with plasma cell dyscrasias. The stimulus for production of AL-amyloid is some disorder of immunoglobulin synthesis (multiple myeloma). B-cell lymphoma, other plasma cells dyscrasias.  AA (amyloid associated) protein. AA protein consists of polypeptides having 76 amino acids and is derived from larger precursor protein in the serum called SAA (serum amyloidassociated protein). In the plasma SAA circulates in association with HDL3 (high-density lipoprotein). SAA is an acute phase reactant protein synthesised in the liver, its level being high in chronic inflammatory and traumatic conditions. It may be in chronic mflammation and cancer, familial Mediterranean fever.
  10. 10. 10 Other proteins. In addition a few other forms of proteins are also found in some types of amyloid  Transthyretin (ATTR) is a serum protein that transports thyroxine and retinol normally while a variant of transthyretin is deposited in familial amyloid polyneuropathies and in senile amyloidosis.  A2-microglobulm (A2m) is amyloid seen in cases on long-term hemodialysis (8-10 years).  -amyloid protein (A) is distinctive from A2m and is seen in cerebral plaques as well as cerebral blood vessels in Alzheimer‟s disease.  Hormone precursor such as procalcitonin and pro-insulin (amyloid endocrine) and keratin has also been reported in amyloid. P-Component The second component of amyloid is non-fibnllar P-component that constitutes about 10% of amyloid material. It is synthesised in the liver and is present in all types of amyloid. It is a glycoprotein resembling the normal serum ar glycoprotein and is PAS-positive Classification of amyloidosis A clinical-pathologic classification is widely used currently. According to this classification, amyloidosis can be divided into 2 major categories each found in distinct clinical settings. A. Systemic Amyloidosis 1. Primary amyloidosis.  This is one of the two types of systemic or generalised amyloidosis.  Primary amyloidosis associates with plasma cell dyscrasias and conteins AL-protein.  In the 25% to 40% of these cases, primary amyloidosis is the high binger of frank plasma cell neoplasia, such as multiple myeloma or other B-cell lymphomas.  Primary amyloidosis is often severe in the heart, bowel, skin, skeletal muscle, and less often in the solid abdominal viscera.  This type of amyloidosis is most common form in the world. 2. Secondary (reactive) amyloidosis.    The second form of systemic or generalised amyloidosis is reactive or secondary in which the fibril proteins contain AA amyloid. Secondary or reactive amyloidosis occurs as a complication of chronic infectious or noninfectious inflammatory conditions associated with tissues destruction such as tuberculosis, bronchiectasis, chronic osteomyelitis, chronic pyelonephritis, leprosy, autoimmune disorders (rheumatoid arthritis, dermatomyositis and scleroderma), inflammatory bowel disease (ulcerative colitis and Crohn‟s disease) and some tumors (renal cell carcinoma and Hodgkin‟s disease). Secondary amyloidosis is typically distributed in solid abdominal viscera like the liver, spleen, kidneys and adrenals Secondary reactive amyloidosis is seen less frequently in developed countries due to containment of infections before they become chronic, but this is the most common type of amyloidosis in underdeveloped and developing countries of the world. 3. Familial amyloidosis.     Familial amyloidosis is seen in patients with familial Mediterranean fever and familial amyloidotic polyneuropathy. Familial Mediterranean fever is an autosomal recessive disease. The condition is characterised by periodic attacks of fever and polyserositis. Amyloidosis occurring in these cases is AA type. Hereditary polyneuropathic amyloidosis is an autosomal dominant disorder in which amyloid is deposited in the peripheral and autonomic nerves. B. Localized Amyloidosis    Senile cardiac amyloidosis is seen in 50% of people above the age of 70 years. The deposits are seen in the heart and aorta. Senile cerebral amyloidosis is deposition of amyloid material in the walls of cerebral blood vessels in 60% of people above the age of 70 years. Patients of Alzheimer‟s disease also develop amyloid in the senile plaques. Endocrine amyloidosis. Some endocrine tumors are associated with microscopic deposits of amyloid in medullary carcinoma of the thyroid, and islet cell tumor of the pancreas. Morphology
  11. 11. 11 Macroscopically, the affected organs are often enlarged and firm and have a waxy appearance. If the deposits are sufficiently large, painting the cut surface with iodine imparts a yellow color that is transformed to blue violet after application of sulfuric acid. The histologic diagnosis of amyloid is based almost entirely on its staining characteristics:  H & E. Amyloid by light microscopy with haematoxylin and eosin staining appears as extracellular, homogeneous, structureless and eosinophilic hyaline material  Metachromatic stains (Rosaniline Dyes). Amyloid has the property of metachromasia, i. e. the dye reacts with amyloid and undergoes a color change. Metachromatic stains employed are rosaniline dyes such as methyl-violet and crystal-violet, which impart rosepink coloration to amyloid deposits.  Congo red. All types of amyloid have affinity for Congo red stain. The stain may be used on both gross specimens and microscopic sections amyloid stains an orange color. The stain can also be used to distinguish between AL and AA amyloid (primary and secondary amyloid respectively). After prior treatment with permangnate on the section, Congo red stain is repeated: in the case of primary amyloid (AL amyloid), the Congo red positivity (congophilia) persists while it turns negative for Congo red in secondary amyloid (AA amyloid).  Sulfated alcian blue. This is a nonspecitic screening test and imparts blue-green color to amyloid positive areas.  lmmunohistochemistry. More recently, immunohistochemical stains can classify type of amyloid. Antibody specific for fibril protein gives positive immunoreactivity. Diagnosis of amyloidosis Histologic examination of biopsy material is the commonest and confirmatory method for diagnosis in a suspected case of amyloidosis. If renal manifestations are present, kidney is the preferred site for biopsy. Otherwise the commonly accessible sites such as rectum, gingiva, and more recently abdominal fat, are biopsied and are followed by Congo red staining for confirmation. Pathologic changes in organs Amyloidosis of Kidneys     Amyloidosis of the kidneys is most common and most serious because of ill-effects on renal function. The deposits in the kidneys are found in most cases of secondary amyloidosis and in about one third cases of primary amyloidosis. The kidneys may be normal-sized, enlarged or terminally contracted due to ischemic effect of narrowing of vascular lumina. Cut surface is pale waxy and translucent. Amyloid deposition occurs primarily in the glomeruli though it may involve peritubular interstitial tissue and the walls of arterioles as well: a) In the glomeruli, the deposits initially appear on the basement membrane of the glomerular capillaries, but later extend to produce luminal narrowing and distortion of the glomerular capillary tuft. b) In the tubules, the amyloid deposits likewise begin close to the tubular epithelial basement membrane. c) The vascular involvement affects chiefly the walls of small arterioles and venules, producing narrowing of their lumina and consequent ischemic effects. Amyloidosis of Spleen Two patterns are observed: “Sago spleen”. The splenomegaly is not marked and cut surface shows characteristic translucent pale and waxy nodules resembling sago grains and hence the name. Microscopically, the amyloid deposits begin in the walls of the arterioles of the white pulp and may subsequently replace the follicles.  “Lardaceous spleen”. There is generally moderate to marked splenomegaly (weight up to 1 kg). Cut surface of the spleen shows map-like areas of amyloid. Microscopically, the deposits involve the walls of splenic sinuses and the small arteries and in the connective tissue of the red pulp. Amyloidosis of Liver. The liver is often enlarged pale, waxy and firm. The amyloid initially appears in the space of Disse, but later as it increases; it compresses the cords of hepatocytes.  Amyloidosis of Heart.
  12. 12. 12  Heart is involved in systemic amyloidosis quite commonly more so in the primary than in secondary systemic amyloidosis. It may also be involved in localised form of amyloidosis in very old patients.  Amyloidosis of the heart may produce arrhythmias due to deposition in the conduction‟s system. The heart shows tiny nodular deposits of amyioid underneath the endocardium.  Later, there may be a pressure atrophy and impaired ventricular function, which may produce restrictive cardiomyopathy. Amyloidosis of Alimentary tract. Involvement of the gastrointestinal tract by amyloidosis may occur at any level from the oral cavity to the anus. Rectal and gingival biopsies are the common sites for diagnosis of systemic amyloidosis. The prognosis for patients with generalized amyloidosis is poor. Those with immunocytederived amyloidosis have a median survival of 2 years after diagnosis. Stromal vascular fatty degenerations  Stromal fatty infiltration is the deposition of mature adipose cells in the stromal connective tissue. The condition occurs most often in patients with obesity.  As a rule it is a generalized process when the amount of fat in the depots increases.  Depending on the excess of the patient mass compared to the norm, 4 degrees of obesity are defined: 1. If the patient‟s mass increases by 20 -29% we distinguish 1st degree of obesity; 2. If the patient's mass increases by 30 -49% - 2nd degree; 3. If the patient's mass increases by 50 - 99% - 3rd degree; 4. If the patient's mass increases by 100% and more 4th degree of obesity.  The two commonly affected organs are the heart and the pancreas.  The damage to these organs is most serious.  Subepicardial fat covers the heart as a case, invades the myocardial stroma causing atrophy and sclerosis.  If the connective tissue does not grow, heart rupture in the area of fat growth may occur.  In pancreatic lipomatosis beta-cell atrophy and diabetes mellitus are possible.  According to the etiology the following types of obesity are defined: 1. Primary (idiopathic); 2. Secondary.  There are several types of secondary obesity: 1. Alimentary. 2. Cerebral. 3. Endocrine. 4. Hereditary in Gierke‟s disease.  According to the patient's appearance, obesity may be 1. Symmetrical 2. Upper 3. Medial 4. Lower.  According to morphological peculiarities of adipose tissue, it may be: 1. Hypertrophic. 2. Hyperplastic. In hypertrophic type adipose tissue enlarges due to increased volume of fatty cells, in hyperplastic due to increase in their number. Obesity is a severe complication of mainly endocrine and nervous diseases. Alimentary obesity is also unfavorable for the organism. As a rule such patients develop ischemic heart disease. Local enlargement of adipose tissue (lipomatosis) occurs in Dercum's disease when painful fat nodes appear in the subcutaneous fat of the lower and upper extremities and trunk. Sharp reduction in the amount of neutral fat in the whole organism is called cachexia. Disturbance in cholesterol and its esters metabolism causes atherosclerosis. The wall of the vessel is thicken everywhere, but much more it is thicken because of the formation of the atherosclerotic plaque, which are composed with lipids and fibrotic tissue. Stromal vascular carbohydrate degenerations Stromal vascular carbohydrate degenerations develop due to disturbance of glycosaminoglycans and glycoproteids metabolism. When glycoproteid metabolism is disturbed,
  13. 13. 13 chromotropic substances are released from the protein bonds. They accumulate in the main substance of the connective tissue. Collagen fibers change into mucus-like mass. Connective tissue mucin is associated with:  Mucoid or myxoid degeneration in some tumors (myxomas).  Neurofibromas, soft tissue sarcomas etc.  Myxomatous change in the dermis in myxedema.  Myxoid change in the synovium in ganglion on the wrist. The condition results in colliquative necrosis with formation of cavities filled with mucus. Mucopolysaccharidoses (MPS)        Disturbance of glycosaminoglycans (GAG) is due to hereditary factors as in a storage disease. It is characterized by deficiency of specific lysosomal enzyme involved in the degradation of mucopolysaccharides or glycosaminoglycans. Syndrome of MPS manifests in infancy or early childhood and involves multiple organs and tissues, chiefly connective tissues, liver, spleen, bone marrow, lymph nodes, kidneys, heart and brain. The mucopolysaccarides accumulate in mononuclear phagocytic cells, endothelial cells, smooth muscle cells and fibroblasts. The material is finely granular and PAS-positive by light microscopy. By electron microscopy, it appears in the swollen lysosomes and can be identified biochemically as mucopolysaccharide. The most frequent of them are Pfaundler-Hurler disease, or gargoilism. Its cause is congenital defect of the enzyme determining GAG metabolism. This disease is characterized by irregular skeleton growth, “massive” skull, heart defects, inguinal and umbilical hernias, hepato- and splenomegaly, keratoleukoma (retina opacity). PATHOLOGY OF PIGMENTS Pigments are colored substances, some of which are normal constituents of cells where as others are abnormal and collect in cells only under special circumstances. Pigments are generally classified into two broad categories:  Endogenous pigments, which are normal constituents of cells and tissues;  Exogenous pigments introduced into the body from environment. Classification of endogenous pigments 1. Hemoglobinogenic pigments. 2. Proteinigenic. 3. Lipidogenic. Pigments derived from hemoproteins appear as a result of physiologic destruction of erythrocytes. Physiologic pigments 1. Ferritin is a ferroproteide. It is located in liver, spleen, bone marrow and lymphatic nodes. 2. Hemosiderin is iron-containing pigment. Hemosiderin, which is formed by aggregates of ferritin and is identifiable by light microscopy as golden-yellow to brown, granular pigment, in the mononuclear phagocytes of the bone marrow, spleen and liver. Hemosiderin is ferric iron that can be demonstrated by Prussian blue reaction 3. Bilirubin is iron-free pigment. Pathologic pigments 1. Hematoidin is iron-free, orange-brown crystal pigment. It‟s formed extravascularly in the center of hemorrhages or foci of necrosis at anaerobic conditions. 2. Hematin is a brown-black pigment derived from hemoglobin and has 2 types:  Chloric hematin is formed in gastric erosions and ulcers as a result of interaction between hemoglobin and gastric excretion (muriate acid).  Hemomelanin is a brown pigment produced by malarial parasites from hemoglobin; it‟s taken up by monocytes in the blood and subsequently deposited in the liver and spleen. 3. Porfirin is precursor of hem. It deposits in blood and urine. Clinical symptoms are photophobia, erythema, and dermatitis. Spleen, bones, teeth, urine becomes of dark red. Porphyria develops when porphyrin metabolism is disturbed. It may be congenital and acquired. Acquired porphyria is
  14. 14. 14 observed in intoxications, avitaminosis (pellagra), pernicious anemia, and diseases of the liver. Pathology of hemosiderin’s metabolism Hemosiderosis Hemosiderosis occurs in two situations: Local hemosiderosis.  It is characterized by local breakdown of red cells in tissues, e.g. in internal hemorrhage.  Mechanism of local hemosiderosis is extravascular hemolysis.  It occurs regularly around areas of bruising and hemorrhage.  In each instance the pigment is localized in cells of the reticuloendothelial system.  In the lungs hemosiderin-laden macrophages (siderofages) are appropriately referred to as “heart failure cells”. Visceral siderosis (systemic hemosiderosis).  Mechanism of systemic hemosiderosis is intravascular hemolysis.  It is seen in the liver, spleen and sometimes in kidneys in cases of hemolytic anemia, and in patients requiring repeated blood transfusion. The generalized form of this condition also referred to as secondary hemochromatosis.  The pigment imparts a deep brown color to tissues and organs when it is present in high concentrations.  It can also occur in patients with chronic ineffective erythropoiesis (such as thalassemia major).  Alcohol ingestion when carried to extremes can lead to hemosiderosis because of the augmentation of iron uptake by alcohol.  In hemochromatosis, a genetic disorder, the absorbtion of iron is virtually uncontrolled. The system becomes overload and iron is deposited as hemosiderin in many sites, the main ones being: - Pancreas – associated with fibrosis, which may destroy islet tissue (diabetes mellitus). - Liver – usually associated with fibrosis (cirrhosis). - Skin – mainly around swet glands. Excessive melanin is also deposited; hence this condition is sometimes termed “bronzed diabetes”. - Heart musle. - Mesenteric lymph nodes. Pathology of bilirubin’s metabolism Jaundice When the bilirubin content of the serum rises above 34 mmol/l, jaundice appears. Types of jaundice 1. Prehepatic jaundice (Hemolytic jaundice) - results from an excessive breakdown of the red blood cell membrane in a variety of conditions, which include:  A genetic membrane defect.  An immune reaction.  Circulating of intravascular toxic substances causing red cell destruction (snake poison).  Hemolytic (familial) jaundice in spherocytosis.  Sickle cell anemia.  Hemolytic disease of the newborn, Rh incompatibility.  Incompatible blood transfusion.  Infections (malaria, clostridial infection, mycoplasma pneumonia, sepsis).  Leukemia. In these conditions the excessive amount of pigment has not pass through the liver for conjugation. The liver‟s capacity to conjugate it is exceeded, and the level of unconjugated bilirubin rises in the plasma. It can crystallize out in the tissues, in the brain, may cause necrosis. Injury of brain may lead to bilirubin encephalopathy (kernicterus). 2. Intrahepatic jaundice (Hepatocellular jaundice) - results from failure both of hepatocytes to conjugate bilirubin and of bilirubin to pass through the liver into the intestine. Both of conjugated bilirubin and unconjugated bilirubin increase its amount in blood. The liver is light yellowish-green color of saffron (“saffron liver”). Failure of conjugation may involve:  Hepatocellular jaundice, e.g., viral hepatitis and hypoxic necrosis.
  15. 15. 15   Drug-induced jaundice, e.g., disturbance of glucoronide conjugation. Intrahepatic cholestasis, e.g., congenital intrahepatic occlusion, tumors, inflammations, or cirrhosis.  Mushroom, arsenic, phosphorous poisoning. 3. Posthepatic jaundice (Obstructive jaundice) - results from an obstruction of the passage of conjugated bilirubin from hepatocytes to the intestine. Conjugated bilirubin is water-soluble and is excreted in the urine. The liver is dark green. Obstructive jaundice may appear in the following causes:  Stenosis of extrahepatic bile ducts.  Gall stones in the major ducts.  Pancreatic tumor compression.  Fibrosis involving the small intrahepatic ducts; the bile ducts became distended with conjugated bilirubin, which is reabsorbed.  In the liver, bile pigments may appear: a) As bile pigment droplets in the hepatocytes. b) As bile impregnations in necrotic areas. c) As bile casts (bile capillaries, cholangioles, or bile canaliculi). d) In Kupffer‟s cells. Pathology of the metabolism of proteinogenic pigments             Melanin is a normal pigment found in the form of fine brown granules in the skin, choroids of the eye, adrenal medulla, and hair and sometimes in the meninges and intestine. Melanin is a brown-black pigment synthesized by melanocytes from tyrosine by its oxidation. After secretion of the pigment, it‟s taken up by adjacent epidermal cells and phagocytic melanophores in the underlying dermis Ultraviolet radiation stimulates the synthesis of melanin. Various disorders of melanin pigmentation cause generalized and localized hyperpigmentation and hypopigmentation. Focal hyperpigmentation: malignant melanoma, nevus, melanosis coli, lentigo. Nevus is a benign tumor. Malignant melanoma is a highly malignant neoplasm that invades normal tissues early and widely and that almost invariably terminates in death. A dysontogenetic malformation (hamartoma) consisting of nevus cells. It‟s frequently presented at birth and grows slowly during puberty. May be generalized melanin pigmentations: a) Addison‟s disease, b) an adrenocortical insufficiency resulting from destruction of the adrenal cortex, c) chloasma observed during pregnancy, d) chronic arsenical poisoning. Localised hypopigmentation: a) leucoderma is a partial albinism and is an inherited disorder; b) vitiligo is hereditary local hypopigmentation of the skin, c) acquired focal hypopigmentation from various causes such as leprosy, healing of wounds, syphilis, radiation dermatitis, etc. Albinism is an inherited generalized disorder of melanin metabolism in which there is a decrease or absence of the pigment in the skin and choroid of the eye. Albinos have blond hair, poor vision and severe photophobia. They are highly sensitive to sunlight. Pathology of the metabolism of lipidogenic pigments    Lipopigments usually include lipofuscin and lipochrom. Lipofuscin is an insoluble lipid pigment presented in cells of elderly persons and those with mulnutrition or a chronic wasting disease. It is a brown intracellular pigment found in hepatocytes, cardiocytes, and neurons. Organs containing large amounts of lipofuscin are deep brown; in the heart, this is referred as brown atrophy. Exogenous pigments Inhaled pigments. The most commonly inhaled substances are carbon or coal dust; others are silica or stone dust, iron or iron oxide, asbestos and various other organic substances. Anthracosis (i. e. deposition of carbon particles) is seen in almost every adult lung and generally provokes no reaction of tissue injury.
  16. 16. 16 Ingested pigments. Chronic ingestion of certain metals may produce pigmentation. Argyna is chronic ingestion of silver compounds. Chronic lead poisoning may produce the characteristic blue lines on teeth. Carotenemia is yellowish-red coloration of the skin caused by excessive ingestion of carrots. Ingested pigments (tattooing). Pigments like India ink, cinnabar and carbon are introduced into the dermis in the process of tattooing where the pigment is taken up by macrophages and lies permanently in the connective tissue. Mineral metabolism disturbance Minerals play an active role in metabolic processes of the human organism. They are components of structural elements of cells, enzymes, hormones, vitamins, and pigments. The most frequent disturbances in medical practice are in the metabolism of calcium, copper, potassium, and iron. Calcium metabolism disturbances I. Dystrophic calcification. Dystrophic calcification refers to the macroscopic deposition of calcium salts in injuried tissues and does not simply reflect an accumulation of calcium derived from the bodies of dead cells. It is often visible to the naked eye, and ranges from gritty, sandlike grains to firm, rock-hard material. Staining with H&E demonstrates calcium salts as deeply basophilic, irregular and granular clumps. For identification of calcium salts we usually use special reaction called silver impregnation method or Kossa‟s method. Calcium deposits are stained black. It may occur in crucial locations, such as: 1. Necrotic tissue, which is not absorbed:  Old caseous lesions of tuberculosis.  Old infarcts.  Old collections of pus.  Dead parasites (echinococci).  Old thrombi.  Dead fetus (lythopedion). 2. Tissues undergoing slow degeneration:  Hyaline areas in simple tumors.  Tissues in old age, especially fibrous tissue, cartilage, in the mitral or aortic valves after rheumatic fever with formation of mitral or aortic stenosis or as in atherosclerotic coronary arteries with narrowing of those vessels. II. Metastatic calcinosis (calcium metastases) reflects deranged calcium metabolism associated with increased serum calcium concentration (hypercalcemia). It has systemic character; its main cause is hypercalcemia, which may be of endocrine origin in hyperproduction of Parathormone or hypoproduction of Calcitonine. Calcium salts precipitate in different organs, more frequently in the lungs, gastric mucosa, kidneys, myocardium, arterial walls. It may be associated with:  Reduction of calcium excretion from the organism.  Multiple fractures of the bones.  Hyperparathyroidism.  Chronic renal failure.  Multiple myeloma.  Osteomalacia (when the bone becomes soft).  Lesions of the large intestine (the place of Ca excretion).  Vitamin D intoxication. The outcome is unfavorable, calcium does not resolve. Copper metabolism disturbance      This appears in Wilson-Konovalov disease (hepatocerebral degeneration, hepatolenticular degeneration). It is a hereditary disease in which liver ceruloplasmin production decreases. Ceruloplasmin is alpha2-globulin and can bind copper in the blood. As a result, copper becomes free from unstable bonds with plasma proteins and sediments in the tissue. Copper accumulates in the liver, brain, kidneys, cornea (in the cornea it looks like greenbrown ring on its margin of the cornea), in the pancreas, testes, etc. The state is characterized by development of liver cirrhosis, degenerative symmetrical changes in the brain in the area of lens nuclei, caudal body, pale globe, and cortex. Copper blood plasma amount is decreased but is increased in the urine.
  17. 17. 17   There are 3 forms of the disease: hepatic, lenticular, hepatolenticular. The outcome is unfavorable. Potassium metabolism disturbances Increased blood (hyperpotassemia) and tissue potassium amount is observed in Addison’s disease and is associated with the lesion of the adrenal cortex, the hormones of which regulate electrolyte exchange. Potassium deficiency characterizes periodic paralysis; hereditary disease for which attack of weakness and motor paralysis are typical. Formation of Stones  Stones or calculi are dense formations freely lying in the cavities of the organs or in the ducts.  Their shape depends on the organs in which they are formed: round in the urinary bladder, facet in the gallbladder (their faces are lapped to each other), branching in the kidneys.  Their surface may be either smooth or rough.  The color depends on their chemical composition: white (phosphates), yellow (urates), dark brown or green (pigment).  On cut they may be crystalloid (radial structure), colloid (stratified structure) and colloidcrystalloid (radial-stratified).  Their chemical composition is different, i.e. biliary stones may be cholesterol, pigment, calcium and combined, urinary - urates, phosphates, oxalates (calcium oxalate), cystin, xantin.  Bronchial calculi consist of mucus inlayed with calcium.  Stones are most frequently formed in the bile ducts and urinary tract in cholelithiasis, urolithiasis, in the excretory ducts of the pancreas, salivary glands, bronchi, crypts of the tonsils, veins (phlebolith), intestine (coprolyth). Both general and local factors are important for pathogenesis of calculus formation. General factors are the main ones; they are acquired or hereditary disturbances of metabolism. Local factors are congestion, inflammation. The immediate mechanism of calculus formation consists of two processes: formation of organic matrix and salt crystallization. Each of these may be primary. Compression with a stone may result in necroses in renal pelvis, gallbladder, bedsores, perforations, inflammation (pyelocystitis, cholecystitis, cholangitis, etc.).
  18. 18. 18 IRREVERSIBLE CELLULAR INJURY: Cell death is a state of irreversible injury. It may occur in the living body as a local change (i. e. autolysis, necrosis and apoptosis), or result in end of the life (somatic death). Autolysis (“self-digestion”) is disintegration of the cell by its own hydrolytic enzymes liberated from lysosomes. Autolysis can occur in the living body when it is surrounded by inflammatory reaction (vital reaction), or may occur as postmortem change in which there is complete absence of surrounding inflammatory response. Autolysis is rapid in some tissues rich in hydrolytic enzymes such as in the pancreas, and gastric mucosa, intermediate in tissues like the heart, liver and kidney, and slow in fibrous tissue. Necrosis Necrosis is celullar death in the living body in the disease. Necrosis is defined as focal death along with degradation of tissue by hydrolytic enzymes liberated by cells. It is invariably accompanied by inflammatory reaction. Two essential changes bring about irreversible cell injury in necrosis - cell digestion by lytic enzymes and denaturation of proteins. Nuclear changes. The irreversibly damaged nuclei are characterized by one of the following three features: 1. At first nucleus shrinks and becomes dense. This process is called karyopicnosis. 2. After that karyorrhexis develops. This process is characterised by rupture of nuclear membrane and fragmentation of the nucleus. Nucleus is decomposed into small granules. 3. Also karyolysis may be developed, when the nucleus dissolves. At electron microscopic level, in addition to the above nuclear changes, disorganization and disintegration of the cytoplasmic organelles and severe damage of the plasma membrane are seen. In the cytoplasm, protein denaturation and coagulation or hydration and colliquation take place. Plasmorrhexis is characterized by decomposition of cytoplasm into clumps due to coagulation. Then plasmolysis takes place. Plasmolysis is hydrolytic fusion of cytoplasm. Sometimes we can observe vacuolization and calcification in the cytoplasm. Stages of necrosis (or morphogenesis): 1. Paranecrosis - reversible changes; as a rule, reversible degeneration. 2. Necrobiosis - irreversible degenerative changes. 3. Death of cells. 4. Autolysis is the enzymic digestion of the dead cell due to effect of catalytic enzymes derived from lysosomes. Types of necrosis    According to the mechanisms of development: 1. Direct (from influence of mechanical, physical, chemical, and toxic factors). 2. Indirect (vascular and neurogenous). According to the cause: 1. Traumatic. 2. Toxic. 3. Trophoneurotic. 4. Allergic. 5. Vascular or ischemic. According to the morphological features: 1. Coagulative necrosis is associated with inhibition of lytic enzymes. Foci of coagulative necrosis in the early stage are pale, firm, and slightly swollen. With progression they become more yellowish, softer, and shrunken. The cells do not lyse; thus, their outlines are relatively preserved. Nuclei disappear and the acidified cytoplasm becomes eosiniphilic. Waxy (Zenker‟s) necrosis of muscle may occur at typhoid fever. 2. Liquefactive (colliquative) necrosis is marked by dissolution of tissue due to enzymatic lysis of dead cells. Typically, it takes place in the brain when autocatalytic enzymes are released from dead cells. Liquefactive necrosis occurs also in purulent inflammation due to the heterolytic action of polymorphonuclear leucocytes in pus. Liquefied tissue is soft, diffluent and composed of disintegrated cells and fluid. 3. Gangrene – develops in organs and tissues having contact with environment. The most often examples of gangrene are gangrene of low extremities, uterus, lungs etc.
  19. 19. 19 There are 3 main forms of gangrene - dry, wet and gas gangrene. Contrasting features of two main forms of gangrene are summarised in Table 1. Sequester – fragment of dead tissue, which can‟t be autolized, replaced by connective tissue and which is localized among alive tissue. 4. Infarction – vascular or ischemic necrosis. 5. Fat necrosis is encountered in adipose tissue contiguous to the pancreas and more rarely at distant sites, as a result of leakage of lipase after acute injury to pancreatic acinar tissue, most commonly from obstruction of pancreatic ducts. Grossly, fat necrosis appears as firm, yellow-white deposits in peripancreatic and mesenteric adipose tissue. Histologically, necrotic fat cells are distinguishable as pale outlines, and their cytoplasm is filled with an amorphous-appearing, faintly basophilic material (soap). 6. Caseous necrosis has features of both coagulative and liquefactive necrosis. Typically, it occurs in the center of tuberculous granulomas, which contain a white or yellow “cheesy” material (Latin caseum = cheese) that accounts for the name of this lesion. Histologically, the outlines of necrotic cells are not preserved, but the tissue has not been liquefied either. The remnants of the cells appear as finely granular, amorphous material. 7. Fibrinoid necrosis is characterised by deposition of fibrin-like material, which has the staining properties of fibrin. It is encountered in various examples of immunologic tissue injury, arterioles in hypertension, peptic ulcer etc. Histologically, fibrinoid necrosis is identified by brightly eosinophilic, hyaline like deposition in the vessel‟s wall or on the luminal surface of a peptic ulcer. Outcomes of necrosis            Regeneration of tissues – replacement of the dead tissue with a new one. Incapsulation – formation of the connective tissue capsula around necrotic area. Organization – replacement of the dead tissue with connective tissue. Petrification – replacement of the dead tissue with calcium salts. Incrustation – replacement of the dead tissue with any other salts except calcium. Ossification – the formation of the bone tissue in the necrotic area; Hyaline change – the appearance of the hyaline-like substance in the necrotic area. Suppuration or purulent fusion of necrotic tissues. Sequestration – formation of sequester. Mutilation – spontaneous tearing- away of the dead tissue. Cystic formation. Apoptosis       Apoptosis is a programmed (physiological) death of the cell in the living body. Morphologic features of apoptosis: 1. Cell shrinkage; 2. Chromatin condensation; 3. Formation of cytoplasmic blebs and apoptotic bodies; 4. Phagocytosis of apoptotic cells or bodies. Histologically, in tissues stained with hematoxylin and eosin, apoptotic involves single cells or small clusters of cells. The apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with dense nuclear chromatin fragments. Because the cell shrinkage and formation of the apoptotic bodies are rapid, however, and the fragments are quickly phagocytosed, degraded, or extruded into the lumen, considerable apoptosis may occur in tissue before it becomes apparent in histologic sections. In addition, apoptosis - in contrast to necrosis - does not elicit inflammation, marking it even more difficulty to detect histologically. The contrasting features of apoptosis and necrosis are summarised in Table 2. TABLE 1. Contrasting features of two main forms of gangrene FEATURE DRY GANGRENE WET GANGRENE
  20. 20. 20 Site Commonly limbs More common in bowel Mechanisms Arterial occlusion More commonly venous obstruction less often arterial occlusion Macroscopy Organ dry shrunken and black Part moist soft swollen rotten and dark Putrefaction Limited due to very little blood Marked due to stuffing of organ with supply blood Line of Present at the junct on between No clear line of demarcation demarcation healthy and gangrenous part Bacteria Bacteria fail to survive Prognosis Generally better septicemia due Numerous present to little Generally poor due to profound toxemia TABLE 2. Contrasting Features of Apoptosis and Necrosis FEATURE 1. Definition APOPTOSIS NECROSIS Programmed and coordinated cell Cell death along with degradation of death tissue by hydrolytic enzymes 2 Causative Physiologic agents processes and pathologic Hypoxia, toxins 3. Morphology No Inflammatory reaction Inflammatory reaction always present Death of single cells Death of many adjacent cells Cell shrinkage Cell swelling initially Cytoplasmic blebs on membrane Membrane disruption Apoptotic bodies Damaged organelles Chromatin condensation Nuclear disruption Phagocytosis of apoptotic bodies by Phagocytosis macrophages macrophages of cell debris by 4. Molecular Lysosomes and other organelles Lysosomal breakdown with liberation changes intact of hydrolytic enzymes and oncossuppressor genes DEATH, SIGNS OF DEATH, POSTMORTEN CHANGES
  21. 21. 21  Death is the expression of irreversible stopping of the vital activity of organism. With approach of death a man turns into the dead body or corpse (cadaver).  There are natural (physiologic), violent death and death after diseases.  Natural death takes place in senile persons as a result of physiologic wear of organism.  Violent death is a result of murders, suicides, traumas and accidents.  Death after diseases is a result of incompatibility of the life with changes that were provoked by pathological (unhealthy) processes.  There are clinical and biological death: 1. Clinical death is characterized with stopping of breathing and blood circulation, which are reversible during some minutes (the time of outliving of the brain cortex). Agony precedes clinical death and is the result of uncoordinated actions of homeostatic systems during terminal period (arrhythmia, paralysis of sphincters, convulsions and pulmonary edema). 2. Biological death is irreversible changes of vital activity of organism and beginning of autolytical processes. The central nervous system dies in the fiirst 5-6 minutes. In other organs and tissues this process lengthen out to some hours or even days. Soon after biological death a number of signs of death and postmorten changes appears. They are the followings:  coolness of the dead body (algor mortis) develops as the result of stopping of warnth‟s production in the body and equilization of temperature of dead body and environment;  becoming numb of a corpse (rigor mortis) is manifested as condensation of arbitrary and nonarbitrary muscles because of disappearing of adenosine triphosphate and accumulation of lactic acid in them. Usually it develops in 2-5 hours after death, spreads to all muscles of the body to the end of the first day, is kept during 2-3 days and then disappears;  putrid drying appears because of evaporation of moisture from the surface of the body. It may be localized or generalized (mummification). The dimness of cornea and appearance of dark-brown patches on sclera are connected with this process;  redistribution of blood in the corpse results in repletion of veins with blood, but arteries remain almost empty. The postmorten coagulation of veins and cavities of the right part of the heart takes place. However in the cases of death because of asphyxia the blood does not coagulate (asphyxia of newborns);  putrid patches appear because of redistribution of blood in the corpse and depend on its position. The blood flows down into the veins of the lower parts of the body and accumulates their. That‟s why putrid hypostases appear in 3-6 hour after death;  putrifacation of the corpse is connected with processes of autolysis and rotting of the corpse. Postmorten autolysis appears earlier and is more expressed in glandular organs which cells are rich in proteolytic enzymes (liver, pancreas, stomach). Patrifacative processes join quickly to postmorten autolysis because of proliferation of putrifactive bacteria. Putrifacation intestifies postmorten autolysis, leading to fusion of tissues which become to be colored in dirty-green color and exhale characteristic putrid smell. Quickness of corpse‟s aulotysis and putrifacation depends on the temperature of environment.
  22. 22. 22 CELLULAR ADAPTATIONS For the sake of survival on exposure to stress, the cells make adjustments with the changes in their environment (i. e. adapt). Broadly speaking, such physiologic and pathologic adaptations occur by  Decreasing or increasing their size (atrophy and hypertrophy respectively).  By changing the pathway of phenotypic differentiation of cells (metaplasia and dysplasia). In general, the adaptive responses are reversible on withdrawal of stimulus. Atrophy Atrophy means reduction of the number and size of cells, tissues and organs in living organism characterized by decrease or stopping their function. Atrophy may be physiologic and pathologic. A. Physiologic atrophy. It is a normal process of aging in some tissues: 1. Atrophy of lymphoid tissue in lymph nodes, appendix and thymus. 2. Atrophy of gonads after menopause. 3. Atrophy of brain. 4. Atrophy of bones. It may be obliteration of the umbilical arteries and arterial duct (Botallow‟s) after birth. B. Pathologic atrophy may be general and local. General atrophy is observed in cachexia due to  Oncologic and chronic diseases.  Starvation.  Injury of hypophysis (endocrine cachexia).  Injury of hypothalamus (cerebral cachexia). Gross appearance of patients occurs:  Sharp exhaustion.  Adipose tissue is decreased and it has brown color.  Muscles are atrophied; skin is dry and flabby.  Internal organs are small, brown color and often shrunken.  Osteoporosis takes place. Histologically:  Cells become smaller in size but are not dead cells.  Shrinkage in cell size is due to reduction in cell organelles.  Accumulation of lipofuscin around nucleus takes place. Lipofuscin (“wear and tear” pigment) is a golden yellow pigment representing undigested lipid material derived from cellular metabolism. Local atrophy has several types: 1. Ischemic atrophy develops due to insufficiency of the blood supply. Hypoxia stimulates of the proliferation of fibroblasts and forms sclerosis. For example: small atrophic kidney in atherosclerosis of renal artery, atrophy of brain in cerebral atherosclerosis. 2. Disuse atrophy (dysfunctional) develops due to reduction of the function of organ: atrophy of muscles due to immobility, atrophy of the pancreas in obstruction of pancreatic duct. 3. Neuropathic atrophy due to interrupted nerve supply: poliomyelitis, motor neuron disease, nerve section, and inflammation of facial nerve. 4. Endocrine atrophy: hypopituitarism may lead to atrophy of thyroid, adrenal and gonads; hypothyroidism may cause atrophy of the skin and its adnexal structures. 5. Pressure atrophy: compression of spine by tumor in nerve root, compression of skull by meningioma arising from pia-arachnoid, compression of sternum by aneurysm of arch of aorta, compression of renal tissue by dilated renal pelvic in hydronephrosis, compression of brain tissue by dilated ventricles in hydrocephalus. 6. Atrophy due to chemical and physical influences. For example: action of the radiation lead to atrophy of bone marrow and genital organs. 7. Idiopathic atrophy: myopathies, testicular atrophy. The atrophic tissue may be replaced by fatty ingrowths. Atrophy is reversible provided the cause is eliminated or deficiencies restored. Hypertrophy and hyperplasia Hypertrophy refers to an increase in the size of parenchymal resulting in enlargement of the organ or tissue, without any change in the number of cells.
  23. 23. 23 Hyperplasia is an increase in the number of parenchymal cells resulting in enlargement of the organ or tissue. Quite often, both hyperplasia and hypertrophy occur together. Mechanisms of hypertrophy  Hypertrophy of tissue arises due to increase of size of functional cells. Thus, the hypertrophied organ has no new cells, just larger cells.  Hypertrophy of tissue arises due to increase of number of functional cells (hyperplasia of cells).  Hypertrophy of cells arises due to both increase of size of functional cells and increase of number of ultrastructural elements. Thus, the increased size of the cells is due not to an increased intake of fluid, called cellular swelling or edema, but to the synthesis of more structural components. It is called true hypotrophy.  False hypertrophy is the increase of the size of organs due to growth of connective tissue, accumulation of the fluid or fatty tissue. It results in atrophy of organ (hydronephrosis, hydrocephalus, obesity of heart). True hypertrophy (hyperplasia) has adaptative and compensative characteristics and may be physiologic and pathologic: A. Physiologic hypertrophy (hyperplasia). 1. Neurogumoral (hormonal) hypertrophy: hypertrophy of female breast at puberty, during pregnancy and lactation, hypertrophy of pregnant uterus, proliferative activity of normal endometrium after a normal menstrual cycle, prostatic hyperplasia in old age. 2. Working hypertrophy of skeletal muscle: hypertrophied muscles in athletes and manual labour. B. Pathologic hypertrophy (hyperplasia). 1. Neurogumoral hypertrophy develops due to impairment of endocrine functions. Endometrial glandular hyperplasia following estrogen excess which it occurs by metrorrhagia; atrophy of testis leads to increase of breast (gynecomastia); hyperfunction of anterior lobus hypophisis (adenoma) leads to increase skeleton (acromegaly). 2. Working hypertrophy develops in tissues consisting of stable undivided cells due to increase of size it one. It may be often in cardiac muscle at some cardiac diseases, such as: systemic hypertension, aortic valve disease (stenosis and insufficiency), mitral insufficiency; hypertrophy of smooth muscle: cardiac achalasia (in esophagus), pyloric stenosis (in stomach), and intestinal stricture; hypertrophy of urine bladder in adenoma of prostatic glands. 3. Compensatory reparative hypertrophy: regeneration of the liver following partial hepatectomy, regeneration of epidermis after skin abrasion; hypertrophy of myocardium in postinfarctional cardiosclerosis. 4. Vicarious (substitutional) hypertrophy: following nephrectomy on one side in a young patient there is compensatory hypertrophy as well as hyperplasia of the nephrons of the other kidney. 5. Hypertrophic vegetations develop due to chronic inflammation in mucous membranes (polyps and condilomas); lymphostasis leads to ingrowth of connective tissue, examples of false hypertrophy. In wound healing, there is formation of granulation tissue. According to stage of adaptation two types of myocardial hypertrophy have been described:  Concentric. In concentric hypertrophy (clinically, no insufficiency) the musculature is clearly enlarged, measuring till 1.8 cm, but chambers of the heart are not dilated.  Eccentric. In eccentric hypertrophy myocardium is enlarged but chambers of the heart are dilated. This leads to hemodynamic disorder with cardiac insufficiency. It is called myogenic dilatation. The affected organ is enlarged and firm. For example: a hypertrophied heart of a patient with systemic hypertension may weight 700-800 g as compared to average normal adult weight of 350 g. There is enlargement of muscle fibers as well as of nuclei. At ultrastructural level, there is increased synthesis. Metaplasia
  24. 24. 24 Metaplasia is defined as a reversible change of one type to another type of adult epithelial or mesenchymal cells, usually in response to abnormal stimuli, and often reverts back to normal on removal of stimulus. Metaplasia is broadly divided into 2 types: A. Epithelial metaplasia. This is the more common type. The metaplastic changes may be patchy or diffuse and usually result in replacement by stronger but less well-specialized epithelium. Some common types of epithelial metaplasia following:  Squamous metaplasia: in bronchus in chronic smokers, in uterine endocervix in prolapse of the uterus and in old age, in gall bladder in chronic cholecystitis with cholelithiasis, in prostate in chronic prostatitis and estrogen therapy, in renal pelvis and urinary bladder in chronic infection and stones; in vitamin A deficiency, apart from xerophthalmia, there is squamous metaplasia in the nose, bronchi, urinary tract, lacrimal and salivary glands.  Columnar metaplasia in which there is transformation to columnar epithelium: intestinal metaplasia in healed chronic gastric ulcer, conversion of pseudostratified columnar epithelium in chronic bronchitis and bronchiectasis to columnar type, in cervical erosion. B. Mezenhymal metaplasia. Less often, there is transformation of one adult type of mesenchymal tissue to another.  Osseous metaplasia. Osseous metaplasia is formation of bone in fibrous tissue, cartilage or myxoid tissue: in arterial wall in old age, in soft tissues in myositis ossificans, in cartilage of larynx and bronchi in elderly people, in scar of chronic inflammation of prolonged duration, in the fibrous stroma of tumor.  Cartilaginous metaplasia. In healing of fractures, cartilaginous metaplasia may occur where there is undue mobility. Dysplasia Dysplasia means “disordered cellular development”, often accompanied with metaplasia and hyperplasia, it is therefore also referred to as atypical hyperplasia. Epithelial dysplasia is characterized by cellular proliferation and cytological changes, which include:  Hyperplasia of epithelial layers.  Disorderly arrangement of cells from basal layer to the surface layer.  Cellular and nuclear pleomorphism.  Increased nucleocytoplasmic ratios.  Nuclear hyperchromatism.  Increased mitotic activity. The two most common examples of dysplastic changes are the uterine cervix and respiratory tract. Healing Healing is the body response to injury in an attempt to restore normal structure and function. The process of healing involves 2 distinct processes:  Complete regeneration (restitution), denoting the replacement of injured cells by cells of the same type, sometimes leaving no residual trace of the previous injury, and  Incomplete regeneration (substitution) or replacement by connective tissue, or fibroplasia, which leaves a permanent scar. In most instances, both processes contribute to repair. In addition, both regeneration and fibroplasia are determined by essentially similar mechanisms involving cell migration, proliferation, and differentiations, as well as cellmatrix interactions. Depending upon their capacity to divide, the cells of the body can be divided into 3 groups:  Labile cells. These cells continue to multiply throughout life under normal physiologic conditions. These include: surface epithelial cells of epidermis, alimentary tract, respiratory tract, urinary tract, vagina, cervix, uterine endometrium, hematopoietic cells of bone marrow and cells of lymph nodes and spleen.  Stable cells. These cells decrease or lose their ability to proliferate after adolescence but retain the capacity to multiply in response to stimuli throughout adult life. These include: parenchymal cells of organs like liver, pancreas, kidneys, adrenal and thyroid; mesenchymal cells like smooth muscle cells, fibroblasts, vascular endothelium, bone and cartilage cells.  Permanent cells. These cells lose their ability to proliferate around the time of birth. These include: neurons of nervous system, skeletal muscle and cardiac muscle cells.
  25. 25. 25 Forms:    Cellular: bones, epidermis, mucous membrane, connective tissue, endothelium, hemopoetic system, and limfoid tissue. Intracellular: myocardium, skeletal muscles, ganglious cells and central nervous system (CNS). Mixed: liver, kidneys, lungs, pancreas, endocrine organs, smooth muscles, vegetative nervous system (VNS). Types: 1. Physiological regeneration is the process of replacement that occurs due to physiologic necrosis (erythrocytes, mucosa). 2. Reparative regeneration (complete, incomplete with regenerative hypertrophy) is the regeneration after some pathologic necrosis. 3. Pathologic regeneration is the slow (hyporegeneration) or pathologically absence one, hyperregeneration or metaplasia (change in cell type). Repair Repair is the replacement of injured tissue by fibrous tissue. Two processes are involved in repair: 1. Granulation tissue formation. 2. Contraction of wounds. Repair response takes place by participation of mesenchymal cells (consisting of connective tissue stem cells, fibrocytes and histiocytes), endothelial cells, macrophages, platelets, and the parenchymal cells of the injured organ. Granulation tissue formation The following 3 phases are observed in the formation of granulation tissue. 1. Phase of inflammation. There is acute inflammatory response with exudation of plasma, neutrophils and some monocytes within 24 hours. 2. Phase of clearance. Combination of proteolytic enzymes liberated from neutrophils, autolytic enzymes from dead tissues cells, and phagocytic activity of macrophages clear of the necrotic tissue, debris and red blood cells. 3. Phase of ingrowth of granulation tissue. This phase consists of 2 main processes: angiogenesis or neovascularisation and formation of fibrous tissue. Angiogenesis (neovascularisation). Formation of new blood vessels at the site of injury takes place by proliferation of endothelial cells from the margins of severed blood vessels. The process of angiogenesis takes place under the influence of the following: 1. Endothelial cell growth factors. 2. Some components of matrix like type IV collagen. Fibrous tissue formation. The new fibroblasts originate from fibrocytes as well as by mitotic division of fibroblasts. Some of these fibroblasts have morphologic and functional characteristics of smooth muscle cells (myofibroblasts). Collagen fibrils begin to appear by about 6th day. As maturation proceeds, more and more of collagen is formed while the number of active fibroblasts and new blood vessels decreases. This results in formation of inactive looking scar known as cicatrisation. Contraction of wounds. The wound starts contracting after 2-3 days and the process is completed by the 14th day. In order to explain the mechanism of wound contraction, a number of factors have been proposed: 1. Dehydration as a result of removal of fluid. 2. Contraction of collagen. 3. Discovery of myofibroblasts. Wound healing    Healing of skin wounds provides a classical example of combination of regeneration and repair described above. Two types of factors influence the wound healing: those acting locally and those acting in general. Local factors: infection, poor blood supply to wound, foreign bodies including sutures interfere with healing and cause intense inflammatory reaction and infection; exposure to ionizing radiation; exposure to ultraviolet light; type, size and location of injury.
  26. 26. 26   Systemic factors: age, nutrition, systemic infection, uncontrolled diabetes, hematological abnormalities. This can be accomplished in one of the following two ways: 1. Healing by first intention (primary union). 2. Healing by second intention (secondary union). Healing by first intention (primary union) This is defined as healing of a wound, which has the following characteristics: Clean and uninfected. Surgically incised. Without much loss of cells and tissue. Edges of wound are approximated by surgical sutures. The sequence of events in primary union is described below: 1. Initial hemorrhage. Immediately after injury, the space between the approximated surfaces of incised wound is filled with blood, which then clots and seals the wound against dehydration and infection. 2. Acute inflammatory response. This occurs within 24 hours with appearance of polymorphs. 3. Epithelial changes. The basal cells of epidermis from both the cut margins start proliferating and migrating towards incisional space in the form of epithelial spurs. 4. Organization. By 3rd day, fibroblasts also invade the wound area. By 5th day, new collagen fibrils start forming. In 4 weeks, the scar tissue with scanty cellular and vascular elements, a few inflammatory cells and epithelialised surface is formed. 5. Suture tracks. Each suture track is a separate wound and incites the same phenomena as in healing of the primary wound.     Healing by second intention (secondary union) This is defined as healing of a wound having the following characteristics: Open with a large tissue defect, at times infected. Having extensive loss of cells and tissues. The wound is not approximated by surgical sutures but is left open. The sequences of events in secondary union are as under:  Initial hemorrhage.  Inflammatory phase. There is an initial acute inflammatory response followed by appearance of macrophages, which clear off the debris as in primary union.  Epithelial changes. As in primary healing, the epidermal cells from both the margins of wound proliferate and migrate into the wound in the form of epithelial spurs.  Granulation tissue. The main bulk of secondary healing is by granulations. Granulation tissue is formed by proliferation of fibroblasts and neovascularisation from the adjoining viable elements.  Wound contraction. Contraction of wound is an important feature of secondary healing, not seen in primary healing.  Presence of infection. Bacterial contamination of an open wound delays the process of healing due to release of bacterial toxins that provoke necrosis, suppuration and thrombosis.    Complications of Wound Healing          Infection. Implantation (epidermal) cyst. Pigmentation. Deficient scar formation. Incisional hernia. Hypertrophied scars and keloid formation. Excessive contraction. Neoplasia. Hematological abnormalities.
  27. 27. 27 HEMODYNAMIC DISTURBANCES These are considered 2 broad headings Disturbances in the volume of the circulating blood. These include hyperemia and congestion, hemorrhage and shock  Circulatory disturbances of obstructive nature. These are thrombosis, embolism, ischemia and infarction.  Hyperemia and congestion Hyperemia and congestion are the terms used for increased volume of blood within dilated vessels of an organ or tissue the increased volume from arterial and arteriolar dilatation being referred to as hyperemia or active hyperemia, whereas the impaired venous drainage is called venous congestion or passive hyperemia. The capillaries and veins are dilated paralytically and filled with blood. Arterial or active hyperemia is caused by an increased supply of blood from arterial system. The affected tissue or organ is pink or red in appearance (erythema). I. Common arterial or active hyperemia is a result  Of increasing volume of circulating blood (pletora).  Of increasing of amount of erythrocytes.  Vacatic (lat. – vacuum) because of decreased atmospheric pressure. II. Local arterial hyperemia can be  Angioneurotic – because of dilatation of arteries and arterioles.  Collateral.  Hyperemia after anemia.  Vacatic.  Inflammatory.  In arterio-venous fistula. Venous, or passive hyperemia, or congestion is caused by impediment to the exit of blood through venous pathway. The dilatation of veins and capillaries due to impaired venous drainage results in passive hyperemia or venous congestion, commonly referred to as congestion. Congestion may be acute or chronic, the latter being more common and called chronic venous congestion. I. Common congestion or Systemic (General) venous congestion is engorgement of systemic veins. It can be a result of  left-sided and right-sided heart failure  diseases of the lungs which interfere with pulmonary blood flow, like pulmonary fibrosis, emphysema, etc.  cardiac decompensation. II. Local congestion can be a result of  venous obstruction because of its thrombosis,  compression of venous vessel with tumor or ingrowth of connective tissue,  development of collateral blood circulation. Morphology of congestion Because of the increase in venous blood, organs become swollen and purplish. With long continued over-distension, the wall of the venules shows reactive thickening and there is mild intestinal fibrosis of the organs, giving them a very firm consistency. These changes are seen typically in the kidney and spleen. Important additional changes are found in the lungs and liver. Lungs. The lungs are burcly, congested and brownish in color. Pulmonary venous engorgement leads to alveolar hemorrhage. Hemoglobin from intra-alveolar blood is transformed into hemosiderin, which is then phagocytized by macrophages. These macrophages are known as heart failure cells. Phagocytes full of brown pigment migrate into intestinal tissue and to the lymph nodus. The sectioned surface is dark brown. It process in lungs is named as “brown induration” of the lungs. Spleen. Chronic venous congestion of the spleen occurs in right heart failure and in portal hypertension from cirrhosis of liver. The spleen in early stage is moderately enlarged while in longstanding cases there is progressive enlargement and may weigh up to 500 g to 1000 g. The organ is deeply congested, tense and cyanotic (“cyanotic induration of the spleen”). Sectioned surface is gray tan. The red pulp shows congestion and marked sinusoidal dilatation with areas of recent and old hemorrhages. These hemorrhages may get organized. This advanced stage seen more commonly in
  28. 28. 28 hepatic cirrhosis is called congestive splenomegaly and is the commonest cause of hypersplenism. Liver. Chronic venous congestion of the liver occurs in right heart failure and sometimes due to occlusion of inferior vena cava and hepatic vein. The liver is enlarged and tender and the capsule is tense. Cut surface shows characteristic “nutmeg liver” due to red and yellow mottled appearance. The changes of congestion are more marked in the centrolobular zone due to severe hypoxia than in the peripheral zone. The centrolobular hepatocytes undergo degenerative changes, and eventually centrolobular hemorrhagic necrosis may be seen. The peripheral zone of the lobule is less severely affected by chronic hypoxia and shows some fatty change in the hepatocytes. If the patient has periods of remission, the remaining liver cells may undergo compensatory hyperplasia. This results in small, irregular, pale nodules alternating with areas of fibrosis – so-called cardiac cirrhosis. It‟s not true cirrhosis and does not causes hepatic failure. Outcomes of congestion:       Edema. Stasis. Hemorrhage. Thrombosis. Induration of organs. Atrophy of organs. Hemorrhage Hemorrhage (i.e. bleeding) is a discharge of blood from the vascular compairtment to the exterior of the body or into nonvascular body spaces. Mechanisms of hemorrhages 1. By destruction of the blood vessel‟s wall (f.e. trauma, rupture of aneurysm). 2. By diapedesis of erythrocytes because of the increased permeability of the vascular wall (f.e. intoxication, hypoxia). 3. By ulceration of the vessel‟s wall (f.e. ulcer of stomach, necrosis of tumor, pulmonary tuberculosis). Thus a severe decrease in the number of platelets (thrombocytopenia) or a deficiency of a coagulation factor (e.g., factor VIII in hemophylia) is assosiated with spontaneous hemorrhages unrelated to any apparent trauma. Types of hemorrhages according to the site of origin 1. Cardiac, as following a penetrating heart wound. 2. Arterial, due to trauma and rupture of a dissecting aneurysm. 3. Capillary, which is usually due to trauma, inherent vessel wall weakness, or a coagulation defect. 4. Venous, which is usually caused by trauma or surgical operation, from esophageal varices. Types of internal hemorrhages     Petechia – a small mucosal or serosal hemorrhage or minute punctate hemorrhage usually in the skin or conjunctiva. Purpura or hemorrhagic infiltration - the accumulation of some erythrocytes in tissue between cells. Ecchymoses or bruise - the superficial large extravasations of blood into the skin and mucous membranes. Following a bruise in association with coagulation defect, an initially purple discoloration of the skin turns green and then yellow before resolving, a sequence that reflects the progressive oxidation of bilirubin released from the hemoglobin of degraded of red blood cells. A good example of an eccxymosis is a “black eye”. Hematoma - a grossly visible localized accumulation of the blood in the soft tissue. Types of hemorrhages in body cavities     Hemothorax – hemorrhage in the pleural cavity. Hemopericardium – hemorrhage in the pericardium cavity. Hemoperitoneum – hemorrhage in the abdomen cavity. Hemoarthrosis – hemorrhage in the joint cavity. External hemorrhages may be such as:
  29. 29. 29    Melena is deposition of the blood in the faces (excrement or stool) due to hemorrhage from ulcer of stomach, polip or ulcer of intestines. Hemoptyesis is hemorrhage from lungs. Metrorrhagia is hemorrhage from uterus. Outcomes of hemorrhages     Coagulation of the blood. Organization and incapsulation of the hematoma. Brown cystic formatiom (in cerebral hematoma due to accumulation of hemosiderin). Purulent fusion of the hematoma. In cases of death from acute massive hemorrhage, the most significant postmorten changes are gross rather then microscopic and consists in generalized pallor of tissue, collapse of the great veins, and a flabby, shrunken, gray spleen. A sudden loss of 33% of blood volume may cause death, while loss of upto 50% of blood volume over a period of 24 hours may not be necessarily fatal. However chronic blood loss generally produces an iron deficiency anemia, whereas acute hemorrhage may lead to serious immediate consequences such as hypovolemic shock. Ischemia Ischemia is a loss of blood supply, which occurs when arterial flow is impeded by atherosclerosis or by thrombi, or by some other causes. Ischemia is the most common cause of hypoxia. Types of ischemia     Angiospastic (reflex). Obstructive. Compressive. Because of redistribution of blood. Morphologic features   The primary response of acute ischemia is cellular swelling or edema with dilation of the endoplasmic reticulum, dissociation of polysomes into monosomes, swelling of mitochondria, and also increased concentration of water, sodium, and chloride and decreased concentration of potassium into the cytoplasm. If the duration of ischemia is short, the structure and the function of tissue may be restored. If ischemia persists, irreversible injury ensures with severe vacuolization of the mitochondria including their christae, extensive damage to cytoplasm membranes, and swelling of lysosomes. When the lesion is continuous, infarction, atrophy or sclerosis may develop. Infarction Infarction is an area of ischemic necrosis within a tissue or an organ, produced by occlusion of either its arterial supply or its venous drainage. Types of infarctions:  Ischemic (white) infarction is encountered with arterial occlusion and in solid tissues (spleen).  Red (hemorrhagic) infarction is encountered with venous occlusion, in tissue as with double circulation, and in tissue previously congested (lung, intestinum).  White infarction with hemorrhagic halo (kidneys, heart). According to their age, infarcts are classified as:  Recent or fresh.  Old or healed. According to the propagation it may be  Total (when the whole organ is affected).  Subtotal (when only a part of the organ is affected).  Microinfarct (when observed only microscopically). Pathogenesis The process of infarction takes place as follows:  Localised hyperemia due to local anoxemia.
  30. 30. 30       Within a few hours, the affected part becomes swollen due to edema and hemorrhage. Cellular changes such as cloudy swelling and degeneration appear early. There is progressive autolysis of the necrotic tissue and hemolysis of the red cells. An acute inflammatory reaction and hyperemia appear at the same time in the surrounding tissues. Blood pigments, hematoidin and hemosiderin, liberated by hemolysis is deposited in the infarct. Following this, there is progressive ingrowth of granulation tissue from the margin of the infarct. Morphologic manifestations Myocardial infarction usually develops due to thrombosis of coronary artery. This infarction shows coagulative necrosis of myocardial cells. Almost no blood is seen in the vessels. The nuclei of muscle‟s fibers and stroma cells are absent. The peripheral portion of the infarction has been invaded by acute inflammatory cells, which act as scavengers and remove the dead cells. It is white infarction with hemorrhagic halo. It is classically irregular shape with hemorrhagic infiltration. Infarction of the lungs. Embolism of the pulmonary arteries may produce pulmonary infarction, though not always. The pulmonary infarcts are classically wedge-shaped with base on the pleura, hemorrhagic, variable in size, and most often in the lower lobes. Fibrinous pleuritis usually covers the area of infarct. Cut surface is dark purple and may show the blocked vessel near the apex of the infarcted area. Old organized and healed pulmonary infarcts appear as retracted fibrous scars. The characteristic feature is coagulative hemorrhagic necrosis of the alveolar walls. Renal infarction is common, found in upto 5% of autopsies. Renal infarcts are often multiple and may be bilateral. Characteristically, they are pale or anemic and wedge-shaped with base resting under the capsule and apex pointing towards the medulla. Generally, a narrow rim of preserved renal tissue under the capsule is spared because it draws its blood supply from the capsular vessels. The affected area shows characteristic coagulative necrosis of renal parenchyma i.e. there are shadows of renal tubules and glomeruli without intact nuclei and cytoplasmic content. Infarction of the spleen is one of the common sites for infarction. Splenic infarction results from occlusion of the splenic artery or its branches. Splenic infarcts are often multiple. They are characteristically pale or anemic and wedge-shaped with their base at the periphery and apex pointing towards hilum. Coagulative necrosis and inflammatory reaction are seen. Occlusion of an artery or vein may have little or no effect on the involved tissue or it may cause death of the tissue and, indeed, of the individual. The major determinates include:  The nature of the vascular supply.  The rate of development of the occlusion.  The vulnerability of the tissue to hypoxia. Clinical significance of infarction Most of the cardiovascular deaths result from myocardial and cerebral infarction. Pulmonary infarction is an extremely common complication in a variety of clinical settings. Ischemic necrosis (gangrene) of the lower extremities is a relatively unusual clinical problem in the population at large but is a major concern in diabetes melitus. Stasis Stasis (stasis - stop) is arrest of blood flow in the vessels of microcirculatory system (capillaries). The capillaries and veins are dilated paralytically and filled with blood. In the lumen of some capillaries the homogenous eosinophilic masses can be seen. They are columns of erythrocytes sticked together, which is called prestasis. Sludge syndrome (phenomenon) is regarded as a type of stasis. It is characterized by sticking of erythrocytes, leukocytes and thrombocytes to each other, which is accompanied by blood viscosity increase. Stasis may be discirculatory as a result of venous hyperemia or ischemia. Causes of stasis:  Physical factors (temperature elevation, cold).  Chemical factors.  Infection.  Infectious-allergic factors.  Autoimmune factors. Short stasis is reversible, long one causes hyaline thrombi formation, vascular permeability increase, edema, bleeding.
  31. 31. 31 Isolated vein spasm may cause leukostasis, accumulation of erythrocytes within venules (small veins) and capillaries. It is observed in hypoxia. In shock, leukostasis may be generalized, but as a rule it is localized in the venules. Microcirculation disturbances. There are four links in microcirculation: 1. The link of inflow and distribution of the blood (arterioles and precapillaries). 2. Intermediate (exchange) link (capillaries). 3. Depot link (postcapillaries and venules). 4. Drainage link (lymphatic capillaries and postcapillaries). The function of microcirculation is exchange between the blood and tissue. Pathology of microcirculatory system is formed of vascular, intravascular and extravascular changes. Vascular changes are those in the thickness and shape of the vessels, angiopathies with disturbance of vascular permeability as a result of hypoxia. Intravascular changes manifest as different disturbances of blood rheology (sludge, prestasis, stasis). They are observed in shock of different origin. Extravascular changes are perivascular edema, hemorrhage, lymphostasis on the lymph vessels. Thrombosis Thrombosis is a pathologic process, which denotes the formation of a clotted mass of blood within the noninterruptured vascular system. Influences predisposing to thrombosis: 1. Injury to endothelium; 2. Alterations in the normal blood flow; 3. Alterations in the blood coagulation system (hypercoagulability). Mechanisms of formation     Agglutination of platelets. Platelets adhere to the endothelium and to each other forming a projecting mass; Agglutination of erythrocytes. If the rate of the blood flow is slow, as in veins, red cells are entangled so that the lumen is occluded; Coagulation of fibrinogen. In front and behind the platelet mass the blood stagnates. Further formation of fibrin takes place resulting in a large solid coagulum. The thrombus extends in either direction to the nearest junction; Precipitation of plasma proteins. With a slow blood flow in the joining vessel more fibrin is formed by the platelets at the tip of the thrombus, thus occluding the joint vessel. Blood stagnates in the joining vessel and thrombosis forwards to the next joining vessel. There may be a succession of thrombotic episodes – a propagating thrombus. Types of thrombi According to the degree of the lumen obstruction, thrombi may be: Occlusive thrombi most commonly develop in small arteries and veins. Wall-attached or parietal thrombi develop in large arteries and heart cavities. Axial. Globe-shaped (in the heart). According to the morphology Thrombi may be of various shapes, size and composition depending upon the site of origin and it is attached to the vascular wall; it is dense, with corrugated surface. It is composed of branching bars of stuck thrombocytes and bands of fibrin with erythrocytes and leukocytes located between them.     Morphological types of thrombi    White thrombus – consists mainly of platelets, fibrin and leukocytes; forms slowly in rapid circulation of the blood (usually in the arteries); Red thrombus – consists of platelets, fibrin and excessive amount of erythrocytes; forms rapidly at slow blood circulation (usually in veins). Venous thrombi are dark-red colored dry masses with dim surface. Mixed or laminated thrombus – has laminated structure, contains white and red elements of thrombus (usually forms in veins, aneurysms of aorta and heart). Mixed

×