Chapter 1

CELLULAR AND TISSUE RESPONSES TO INJURY

39

Abnormal metabolism

A

Normal cell Protein mutation

Fatty liver

Protein folding, transport

B

Lack of enzyme

Complex Soluble substrate products Enzyme

Complex substrate Lysosomal storage disease: accumulation of endogenous materials

C

Ingestion of indigestible materials

of process is fatty change in the liver because of intracellular accumulation of triglycerides (described in a later section). Another example is the appearance of reabsorption protein droplets in the epithelial cells of renal proximal tubules because of increased leakage of protein from the glomerulus. 2. A normal or abnormal endogenous substance accumulates because of genetic or acquired defects in the metabolism, packaging, transport, or secretion of these substances. One example is the group of conditions caused by genetic defects of specific enzymes involved in the metabolism of lipid and carbohydrates resulting in intracellular deposition of these substances, largely in lysosomes in so-called storage diseases. Another is α1-antitrypsin deficiency, in which a single amino acid substitution in the enzyme results in defects in protein folding and accumulation of the enzyme in the ER of the liver in the form of globular eosinophilic inclusions. 3. An abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulations of carbon particles and nonmetabolizable chemicals such as silica particles are examples of this type of alteration. Whatever the nature and origin of the intracellular accumulation, it implies the storage of some product by individual cells. If the overload is due to a systemic derangement and can be brought under control, the accumulation is reversible. In genetic storage diseases, accumulation is progressive, and the cells may become so overloaded as to cause secondary injury, leading in some instances to death of the tissue and the patient.

LIPIDS
HEPATIC LIPIDOSIS (FATTY LIVER, FATTY CHANGE, HEPATIC STEATOSIS)
Accumulation of exogenous materials

D

Fig. 1-43 Mechanisms of intracellular accumulations. A, Abnormal metabolism, as in fatty change in the liver; B, mutations causing alterations in protein folding and transport, as in α1-antitrypsin deficiency; C, deficiency of critical enzymes that prevent breakdown of substrates that accumulate in lysosomes, as in lysosomal storage diseases; and D, inability to degrade phagocytosed particles, as in hemosiderosis and carbon pigment accumulation.
(A through D, From Kumar V, Abbas A , Fausto N: Robbins & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders.)

All major classes of lipids can accumulate in cells: triglycerides, cholesterol/cholesterol esters, and phospholipids. Phospholipids are components of the myelin figures found in necrotic cells. In addition, abnormal complexes of lipids and carbohydrates accumulate in the lysosomal storage diseases. Lipidosis is the accumulation of triglycerides and other lipid metabolites (neutral fats and cholesterol) within parenchymal cells. Although it occurs in heart muscle, skeletal muscle, and the kidney, clinical manifestations are most commonly detected as alterations in liver function (elevated liver enzymes, icterus) because the liver is the organ most central to lipid metabolism. Hepatic lipidosis, the prototype example of this type of cellular degeneration, can occur as the result of one of five mechanisms:

Impaired synthesis of apoprotein (CCl4 toxicity. In hepatocytes . provide a large component of the basal energy needs for parenchymal cells. Fausto N: Robbins & Cotran pathologic basis of disease. Alterations in one or Free fatty acids Uptake Acetate Fatty acids Catabolism α-Glycerophosphate Oxidation to ketone bodies. from chylomicrons in the blood. Impaired release (secretion) of lipoproteins from the hepatocyte (uncommon) The underlying pathogenesis of hepatic lipidosis centers on the biochemical pathways of free fatty acid formation and metabolism. or from adipose cells in body fat stores (adipose tissue). such as diabetes mellitus (increased mobilization of triglycerides). These gross lesions are attributable to the accumulation of glycogen and water in the cytoplasm of hepatocytes (see Chapter 8). respectively). and adipose tissue. protein-calorie malnutrition (impaired apolipoprotein synthesis). Chylomicrons transport dietary lipids consisting predominately of triglycerides from the alimentary system to the liver. yellow. but it is pale beige to tan-white. such as feline hepatic lipidosis (feline fatty liver syndrome) and fat cow syndrome. Decreased β-oxidation of fatty acids to ketones and other substances because of mitochondrial injury (toxins. Excessive delivery of free fatty acids either from the gut or from adipose tissue 2. such as glycogen storage (Niemann-Pick disease [phospholipid sphingomyelin]) and Wilson’s disease. a 1-cm-thick transverse section from a liver lobe may float in formalin. The liver in glucocorticoid hepatopathy is also enlarged and has rounded edges. free fatty acids are esterified to triglycerides. hepatocytes with lipidosis are vacuolated. the cut surface of severely affected livers can bulge and the hepatic parenchyma is soft and friable and has a greasy texture attributable to lipid within hepatocytes. B). 1-46. and starvation (increased mobilization of triglycerides). such as CCl4 (carbon tetrachloride is used in industrial applications) and yellow phosphorus (used in manufacturing other products) for example (rarely seen in clinical medical practice today). 2005. Such conditions usually occur when there is increased demand for energy over a short duration. which are attributed to the hydrophobic interface between water and lipid in the cell’s cytoplasm and should be compared with vacuoles that result from glycogen accumulation (Fig. hypoxia) 3. converted into cholesterol or phospholipids. mild fatty change may not be detectable. hepatic lipidosis most commonly arises from conditions that cause increased mobilization of body fat stores. They are obtained directly from the diet through digestive processes. Cut sections do not float in formalin. Lipoprotein lipase and other proteins act synergistically within the chylomicron to free fatty acids from triglycerides for their use as an energy source. Hepatic lipidosis is also observed with nutritional disorders including obesity (increased transport of dietary lipids or mobilization from adipose tissue). A). but livers with notable lipidosis are enlarged.) more of these biochemical processes can result in the accumulation of triglycerides and other lipid metabolites. (From Kumar V. catabolism. but it also occurs in genetically inherited disorders. Free fatty acids. aflatoxicosis) 4. Grossly. and nongreasy (Fig. Philadelphia. derived from triglycerides. 1-44 Fatty liver. Microscopically. Saunders. In addition. with the extent of the vacuolation depending on the severity of the lipidosis. can also induce hepatic lipidosis via decreased oxidation of free fatty acids. In domestic animals. Abbas A . as in late pregnancy and early lactation in dairy cows (pregnancy toxemia and ketosis. Initially there are a few small clear vacuoles that increase in size and number and eventually coalesce into larger vacuoles. When incised. Defects in any of the steps of uptake. B). These vacuoles have sharply delineated borders (Fig. Triglycerides can only be transported out of hepatocytes if apolipoprotein converts them to lipoproteins (Fig. again indicative of lipid within hepatocytes. Certain chemical agents. CO2 Phospholipids Cholesterol esters Triglycerides Apoprotein Lipoproteins Secretion Lipid accumulation Fig. 1-46. A). and the edges of the lobes are rounded and broad instead of sharp and flat (Fig. Schematic diagram of the possible mechanisms leading to the accumulation of triglycerides in a fatty liver. or secretion can result in lipid accumulation in the cell. resulting in hepatic lipidosis. the cause of hepatic lipidosis is unclear. and in endocrine disease. 1-45. 1-44). It is important to distinguish these gross lesions from the lesions present in glucocorticoid (steroid) hepatopathy in dogs. muscle. ed 7. In the liver. 1-45. firm. or oxidized to ketones. In some disorders.40 SECTION I GENERAL PATHOLOGY 1. Impaired combination of triglycerides and protein to form lipoprotein (uncommon) 5. soft and friable.

College of Veterinary Medicine.Chapter 1 CELLULAR AND TISSUE RESPONSES TO INJURY 41 A B Fig. K. but as alcohol and clearing agents used during the processing of paraffin-embedded sections dissolve fat. In extremely affected livers in which all of the hepatocytes are filled with lipid. The liver is usually enlarged and the edges rounded. (A and B. 1-45 Steatosis (fatty liver. J. Vacuoles in hepatocytes may be due to fat accumulation but can also occur as the result of intracellular accumulation of glycogen or water. B. Courtesy Dr. The cut surface bulges on incision and may feel greasy. M. College of Veterinary Medicine. the liver can resemble fat and can be identifiable only by the presence of portal areas. hepatic lipidosis). dog. all hepatocytes are vacuolated and their nuclei have been displaced to the side. (A. M. Cullen. McGavin. This cut surface would bulge on incision and not be greasy. which are alcoholic solutions of fat soluble dyes. Vacuoles that do not stain with either fat or PAS are presumed to be a result of the accumulation of water (hydropic degeneration). Courtesy Dr. Fat stains. A. liver. Note the swollen hepatocytes (arrows) with extensive cytoplasmic vacuolation. A B Fig. University of Illinois. University of Tennessee. Fat is confirmed by special stains. include Sudan III. H&E stain. 1-46 Glucocorticoid hepatopathy. the nucleus can be displaced to the periphery. fatty change. B.) . North Carolina State University. and Oil-Red-O. ox.D. liver. The liver is usually enlarged and the edges rounded. B. Courtesy Dr. Note the uniformly pale yellow surface. and the cell can resemble an adipocyte. A. H&E stain. Extensive accumulation of glycogen in hepatocytes leads to an enlarged and pale brown to beige liver in dogs with glucocorticoid excess from endogenous (Cushing’s disease) or exogenous sources. Bailey. In this severely affected liver. College of Veterinary Medicine. formalin-fixed frozen sections—properly stained for fat—must be used to confirm the presence of fat in hepatocytes. Scharlach R.) with large amounts of fat. Glycogen is confirmed by the PAS and PAS-diastase reactions described later (see Glycogen).

glycogen is found not only in hepatocytes but also in the epithelial cells of renal proximal tubules and in B cells of the Islets of Langerhans. 1-46). Glycogen (purplish-red) is uniformly dispersed throughout the cytoplasm of all hepatocytes. In contrast to intracellular fat whose vacuoles are rounded and sharply delineated. and the type of fixation. in which the lipid is intracellular (see previous discussion). However. 1-47. and the tissue section on the second glass slide is untreated. when overloaded with glucose. (A and B. the delay between death and fixation during which time the glycogen is metabolized. A). Courtesy Dr. such as diabetes mellitus. so-called polarization of glycogen.) distortion of tissues attributed to fixation in alcoholic fixatives and also avoids “polarization. Histologically. if very large amounts of glycogen are stored in hepatocytes.2-glycol linkages to form aldehydes. Ten-percent buffered neutral formalin fixation at 4° C. Exactly which cells store glycogen depends on the defective enzyme. M. and hyperglycemia leads to increased glycogen concentration in these cells. Periodic acid–Schiff technique. Microscopically the amount of glycogen demonstrated in hepatocytes is chiefly a function of the original concentration in the cell. A B GLYCOGEN Variable amounts of glycogen are normally stored in hepatocytes and myocytes (the amount in the liver depends on the interval between sampling and the last meal).g. In diabetes. but skeletal muscle is frequently involved (see Chapters 14 and 15 for more detail). which are revealed by Schiff ’s reagent. B). Grossly. glycogen appears as clear vacuoles in the cytoplasm of the cell. large amounts of glucose are passed out in the glomerular filtrate and exceed the resorptive capacity of the renal tubule epithelial cells. Adipocytes are normally present in connective tissue and in limited numbers between fasciculi of skeletal muscle and subepicardially between cardiac myocytes. glycogen is demonstrated specifically by the PAS reaction using two serial tissue sections mounted on glass slides. When increased lipid is to be stored. Thus the deposits digested by diastase are glycogen. liver. The PAS reaction breaks 1. Also in diabetes.” the phenomenon whereby the glycogen is displaced to the side of the cell away from the surface.42 SECTION I GENERAL PATHOLOGY FATTY INFILTRATION Fatty infiltration should not be confused with fatty change or steatosis. . The tissue section on the first slide is pretreated with diastase. absolute alcohol or 10% formalin in absolute alcohol). Despite frequent statements that glycogen is best preserved by fixing tissue in an alcoholic fixative (e. the liver may be enlarged and pale (Fig. It occurs in old age and in obesity in which there is hyperplasia of adipocytes by means of proliferation of preadipocytes. sometimes in massive amounts in cells as a result of a defective enzyme. hence the use of two slides including one pretreated with diastase to specifically identify glycogen. When myocytes of skeletal muscle atrophy and disappear. 1-47. These linkages occur in substances other than glycogen. Hepatocytes are highly permeable to glucose. glycogen accumulates. McGavin. physiologic deposits of glycogen cannot be detected. College of Veterinary Medicine. 1-47 Glycogen. The glycogen in each hepatocyte has been pushed to the side of the cell. This procedure retains most of the glycogen but avoids the excessive shrinkage and Fig. the lost myocytes may be replaced by adipocytes (see Fig. adipocytes increase in number. glycogen forms irregular clear spaces with indistinct outlines. In glycogen storage diseases (glycogenoses). Absolute alcohol (ethanol) fixation at room temperature. Periodic acid–Schiff technique.D. A. dog. where massive amounts of glycogen are stored. Large amounts of glycogen can be found in the livers of young growing animals and in animals that are well nourished and on diets of commercially produced feeds. as in steroid-induced hepatopathy. glycogen can be well preserved by fixation in an ordinary 10% buffered neutral formalin solution at 4° C in a refrigerator during the period of fixation (Fig. and the process is called fatty infiltration. Microscopically. 15-29). University of Tennessee. Polarization is seen in fixation at room temperature but is worst with alcoholic fixatives (Fig. which accumulates intracellularly. Hepatocytes of starved animals are usually devoid of glycogen. which digests the glycogen in the tissue.. These cells. hepatocyte nuclei may be displaced peripherally. or in animals that have received excess amounts of corticosteroids. B. Usually the nucleus remains centrally located in the hepatocyte. but in steroid-induced hepatopathy. Excessive amounts of glycogen are present in animals in which glucose or glycogen metabolism is abnormal. convert it into glycogen.

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