Fatty Change, Pigmentation & Mineralization PDF

Intracellular Accumulations Under some circumstances, cells may accumulate abnormal amounts of various substances. These may be harmless or may cause injury The location of the substance may be either in the cytoplasm, within organelles (lysosomes), or in the nucleus There are three pathways by whic...

Intracellular Accumulations Under some circumstances, cells may accumulate abnormal amounts of various substances. These may be harmless or may cause injury The location of the substance may be either in the cytoplasm, within organelles (lysosomes), or in the nucleus There are three pathways by which cells can accumulate abnormal substances 1. A normal substance may be produced at a normal or an increased rate, but the metabolic rate is inadequate to remove it. An example of this type is fatty change in the liver 2. A normal or an abnormal endogenous substance accumulates because of genetic or acquired defect in its metabolism, transport, or secretion. Example: A genetic enzymatic defect in a specific metabolic pathway resulting in disorders called "lysosomal storage diseases". 3. An abnormal exogenous substance may accumulate because the cell has neither the enzymes to degrade the substance nor the ability to transport it to other sites. Examples: accumulations of carbon (anthracosis), or silica particles (silicosis) in the lungs.  Fatty Change Any abnormal accumulation of neutral fat within parenchymal cells It is reversible change, but if the cause is not removed, it may lead cell death It is more commonly seen in liver as liver is the major organ involved in fat metabolism But it can also be seen in heart, kidneys etc.. Etiology: Fatty change is caused by a variety of irritants: Hepatotoxins; both organic and inorganic substances may cause fatty change, bacterial toxins, plant toxins, chemical toxins, in human alcohol is the most important hepatotoxin  Metabolic diseases; such as diabetes mellitus 4. Deficiency of lipotropic factors; choline is a lipotropic factor which is required for the transformation of neutral fat into phospholipids Its deficiency leads to reduced transformation of neutral fats, and accumulation of neutral fats in body tissues Methionine is a choline precursor and also considered as lipotropic factor 5.Obesity  Pathogenesis Abnormal accumulation of triglycerides or neutral fats within liver may result from defect in any one of the following events: 1. excessive entry of fatty acids into the cell 2. Enhanced fatty acid synthesis 3. Increased esterification of fatty acids to triglycerides 4. Decreased apoproteins synthesis, apoproteins are required or the conversion of triglycerides into lipoproteins and their excretion from the cells 5. Impaired lipoprotein secretion from the cell  Macroscopic appearance Most commonly seen in liver Yellow appearance of the liver Color of organ depends upon the natural color of fat in that species of animal In cat, it is white; in cattle it is yellow; in horse it is orange As the liver enlarges, its borders become rounded Consistency; it becomes soft and greasy Liver easily ruptures Cut surface bulges out, with greasy appearance  Microscopic appearance Small clear vacuoles of varying size are seen in the cytoplasm Small vacuoles may combined together and form larger vacuoles, it indicates severe and chronic injury Water and glycogen may also appear as clear vacuoles, Oil Red-O or Sudan IV stains are used for fat, while Periodic Acid-Schiff reaction is used to identify glycogen Pigmentation  Pigments Pigments are colored substances which are found in the cells Some are normal, such as melanin which produces skin color Pigments may be endogenous or exogenous Endogenous pigments Synthesized or originated within the body Include; melanin, lipofuscin, derivatives of hemoglobin  Melanin Brown to black pigment produced in melanocytes Enzyme tyrosinase causes oxidation of tyrosine amino acid Melanocytes are present in the basal layer of the epidermis Stored as minute black or brown granules in the epithelial cells of Stratum germinativum Melanin appear black, brown or red depending upon its concentration and distribution in the skin Melanin protects against harmful ultraviolet rays Cells which store melanin are called melanophores  Melanosis—during early development, foci of melanocytes become located in various internal organs such as intestines, lungs hearts, it is know as melanosis Melanosis of cornea may cause blindness in some breeds of dogs Abnormal increased amount of melanin pigment is seen in melanocyte tumors (malignant melanoma or melanocarcinoma) Acanthosis nigricans—an increased amount of melanin in skin Albinism—it is complete absence of melanin pigment in an individual, melanocytes are present but unable to produce melanin due to inherited deficiency of tyrosinase enzyme, the individual is known as albino Leukoderma—it is localized loss of pigment, only some parts of body are affected Vitiligo---partial or complete absence of melanocytes  Derivatives of hemoglobin Average life of an erythrocyte is 120 days Destruction of erythrocytes takes place in mononuclear phagocytic cells of, spleen, liver and bone marrow Three components are released globin, iron and heme Globin is soluble in tissue fluids and is recycled through lymph and blood Iron is stored in the body in form of ferritin and hemosiderin When there is excess of iron, ferritin forms hemosiderin granules which are visible under light microscope  Hemosiderin Hemoglobin derived golden yellow to brown pigment Local accumulation of hemosiderin results from local hemorrhage Best example is bruise (a type of physical injury to skin), firstly the area is red-blue due to hemorrhage, then due to erythrocyte destruction it becomes green-blue (biliverdin, green bile), then turns into golden-yellow (hemosiderin) systematic hemosiderin accumulation may be seen in various body organs and condition is known as hemosiderosis It may be associated with increased dietary intake of iron Decreased utilization of iron, hemolytic anemia  Bilirubin A pigment derived from hemoglobin but contains no iron It is major pigment of bile About 70% bilirubin is derived from destruction of RBCs in liver, spleen, bone marrow Remaining 30% bilirubin is derived from non-hemoglobin heme proteins (hemoproteins) such as P-450 cytochromes Heme is oxidized to biliverdin by enzyme heme oxigenase Then biliverdin is reduced to bilirubin by enzyme biliverdin reductase This conversion takes place in mononuclear phagocytes, mainly in spleen The bilirubin is complexed with albumen and transported to liver Birds secrete biliverdin only because they lack the enzyme biliverdin reductase  In the liver, bilirubin is conjugated with the help of enzyme glucuronyl transferase Conjugated bilirubin is secreted into bile canaliculi Unconjugated bilirubin is toxic to the tissues, insoluble in aqueous solution, and is tightly bound with albumin While conjugated bilirubin is non toxic, soluble in water and loosely bound to the albumin Then bilirubin flows in the bile and reaches in the intestine, here with the help of bacterial action, it is converted into stercobilin, and excreted in the feces and give color to the feces Urobilin: A small amount also reaches to kidneys and excreted in urine  Jaundice Jaundice or icterus is the yellow discoloration of skin and sclera (eye) that occurs when bilirubin level is elevated in blood (hyperbilirubinemia) Bile pigments may also be excreted in the urine Jaundice occurs when balance between the bilirubin production and clearance is disturbed, this disturbance may be caused by: 1. overproduction of bilirubin by increased breakdown of RBCs 2. reduced uptake by liver due to intrahepatic lesions 3. impaired conjugation that may be due to genetic lack of glucuronyl transferase 4. impaired intrahepatic secretion of bilirubin 5.impaired extrahepatic secretion of bilirubin Frist three mechanisms produce unconjugated hyperbilirubinemia while the last two produce conjugated hyperbilirubinemia  Types of Jaundice Depending upon the location of problem/lesion causing hyperbilirubinemia, jaundice can be divided into three types: 1. hemolytic (prehepatic) 2. toxic (intrahepatic) 3. obstructive (posthepatic) 1. hemolytic (prehepatic) In this case serum bilirubin is unconjugated It may caused by three mechanisms; A. overproduction of bilirubin, due to increased destruction of erythrocytes caused by blood protozoa such as Babesia, Anaplasma, Trypanosoma etc.. some viral diseases like infectious viral equine anemia, bacterial toxins like Clostridium hemolyticum In this case, bilirubin is unconjugated, and due to its larger molecular size, it is not present in the urine  B. reduced hepatic intake of bilirubin 2. toxic (intrahepatic) jaundice This occurs in case of injury to hepatocytes or hepatitis (inflammation of liver) Bacteria (salmonella, leptospira), viruses, plant toxins, Conjugation and secretary mechanisms are impaired 3. obstructive (posthepatic) jaundice Caused by mechanical obstruction in the flow of bile This obstruction may be caused by hepatic parasites (Fasciola hepatica) or gall stones Tumors may also cause obstruction in the bile flow Characterized by conjugated hyperbilirubinemia Urine also contains bilirubin, as conjugated bilirubin is of smaller size and thus filtered  Bile Pigments Hemorrhage or hemolysis biliverdin – by bilivedin reductase – bilirubin + albumin (hemobilirubin) In the liver cleaved from albumin and conjugated - with glucoronic acid – through uridine diphosphoglucose glucuronyl transferase – bilirubin diglucuronide (conjugated bilirubin) In the intestines reduced by bacteria to urobilinogen Some urobilinogen is reabsorbed into the portal circulation and carried to the liver and re-secreted into intestines Rest is excreted in urine Some of it is oxidized to urobilin and stercobilin  Exogenous pigments Pigments coming from outside the body The lungs and their lymph nodes are reservoir of various dust particles Lung disorders caused by the inhalation of any aerosol or dust particles are collectively known as pneumoconiosis, it is often associated with occupation, therefore also known as occupational diseases, various types are as follows: A. Anthracosis; deposition of carbon or coal dust in the lungs Seen in animals, and Human working in coal mines Air pollution in industrial areas may lead to Anthracosis Macroscopically, lungs are black Microscopically, carbon particles are contained within macrophages Carbon is insoluble in body tissues, so pigment persists for life  B. siderosis; deposition of iron in the lungs Seen in animals and human working in iron mines Macroscopically, lungs appeared as brown or rusty red color Microscopically, iron occurs as brown or black irregularly shaped granules within macrophages C. silicosis; deposition of silicon or stone dust in the lungs More common in human Silicon is powerful irritant and causes severe fibrosis (increased connective tissue) It predisposes lungs to tuberculosis (TB) Macroscopically, lungs show small, discrete nodules Mineral Deposits  Pathological Calcification Dystrophic Calcification Degenerating and necrotic tissue Metastatic Primary hyperparathyroidism Secondary Renal disease (excretion of P is reduced) Excessive Vit. D in diet - Yellow Dystrophic calcification in the wall of the stomach oat – excess Vit. D Purple (Blue) color with HE Von Kossa "metastatic calcification" in the lung  Gout Uric acid and urates are end products of purine (adenine and guanine) metabolism Humans and birds An increase in the level of serum uric acid may result from overproduction or reduced excretion of uric acid, or from both Whatever the cause increased levels of uric acid in the blood and other body fluids (e.g., synovium) lead to precipitation of monosodium urate crystals. Precipitation of the crystals, in turn, triggers a chain of events that end in joint injury The released crystals are chemotactic and also activate complement This results in the generation of C3a and C5a, which induce accumulation of neutrophils and macrophages in the joints and synovial membranes Phagocytosis of crystals causes release of toxic free radicals and leukotrienes, particularly B4  Death of the neutrophils releases destructive lysosomal enzymes. Macrophages also participate in joint injury. After ingestion of urate crystals, macrophages secrete a variety of proinflammatory mediators, such as interleukin-l, IL-6, IL-8, and tumour necrosis factor (TNF) These not only intensify the inflammatory response, but also activate synovial cells and cartilage cells to release proteases (e.g., collagenases) that cause the tissue injury. This is how develops an acute arthritis Tophi ( aggregates of uric acid crystals)