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Specific types of intracellular degenerative changes

1. (Acute) cellular swelling (急性)細胞腫脹 [ related stuff ]

    --- One of the earliest recognizable events following injury

 
              ----------------------------------------------------------------------------

                  # Stimulus

                      ---> Irritation

                               --------------------------------------------> Cellular swelling

                                   (Maintained toxic stimulus)

              ---------------------------------------------------------------------------------------------- 
 

    1) Occurrence

          --- Epithelial and endothelial cells

                  --- Liver/ Kidney

    2) Morphological findings

        (1) Gross findings

               --- Some pallor

                    Increased turgor
 

                    Increased organ weight

                         <--- Enlargement of organ

                                    --- Difficult to recognize

        (2) Light microscopic appearance

              --- Seemingly the increased cellularity  due to the increased cellular volume

                   Compression of microvasculature

                       --- Hepatic sinusoids

                                --- Narrowed " Disse space "

              --- Dullness of cytoplasm due to the dilution by the inflow of water

                      --- Loss of glycogen

                               --- Glycolysis

             Electron microscopic appearance

              --- Change in cell membrane

                       --- Surface extrusions(Blebs)

                                <--- Increased entropy

                   Distortion of specialized structure on the membrane

                       --- Microvilli

              --- Expanded cytoplasm without increase in number of organelles

                       --- Focal or diffuse lysis of protoplasm

                   Mitochondrial swelling

                   Dilatation, vesiculization and fragmentation of ER

              --- Changes in nucleus

                      --- Swelling

                           Dispersion of chromatin

                           Disruption of nucleoli

    3) Pathogenesis

          --- All types of injurious agents

                  ---> A failure of the ionic pump mechanism

          --- Na-K ATPase damage

                  ---> Depression of energy production

                             ---> Paralysis of sodium pump

          --- Paralysis of sodium pump

                  ---> Influx of Na⁺, Cl^_ or Ca²⁺

                         Influx of plasma proteins

                         ===> Acute cellular swelling

                                    ---> Leakage of intracellular enzymes into plasma
 

                 -------------------------------------------------------------------------------

                  # Na-K ATPase -----------> Transformation of structure

                                                 ATP        ---> Na⁺ out/ K⁺ in

                  # Physical/ chemical/ or immunological injury

                       ---> Immediate loss of membrane integrity

                                  ---> More rapid cellular swelling

                                              <--- Before a drop in ATP
                 --------------------------------------------------------------------------------

    4) Significance and effect

          --- An indicator of mild injury

               A possible antecedent to more severe cell injury

          --- A reversible alteration

               No significant functional effect

          --- Release of intracellular enzymes

                   --- GOT/GPT ...

                 -------------------------------------------------------------------------------

                  # Death due to influx of Ca²⁺

                       --- Loosening of gap junction extracellularly

                       --- Depolymerization of cytoskeleton

                              ---> Loss of microfilaments and microtubules

                                        ---> Paralysis of cellular function

                 -------------------------------------------------------------------------------
 

               Activation of phospholipase

                    ---> Destruction of membrane

    5) Types of cellular swelling

        (1) Cloudy swelling 混濁腫脹

               --- An old term

               --- An uniformly swollen, cloudy appearance of the cytoplasm

                        --- Microscopic appearance of unstained preparation

               --- Needed to differentiate from autolysis

        (2) Hydropic or vacuolar degeneration 水泡性 또는 空胞變性

              --- More severe than cloudy swelling

                       --- More severe acute cellular swelling

              --- Vacuolar or ballooning degeneration
 

              --- Occurrence

                       --- Epithelium

                               --- Proximal convoluted tubules

                                    Liver

                                       <--- Chloroform or CCl₄ poisoning

                                              Certain infections

                                              High fevers

                                              Hypokalemia

                               --- Associated with epithelial lesions

              --- Microscopic appearance

                      --- Small cleared vacuoles within the cytoplasm

                               --- Distended/pinched-off or sequestered segments of the ER

                      --- Should be differentiated from

                               --- Cloudy swelling

                                    Fatty degeneration

                                    Glycogen

                                    Autolysis

                                    Artifacts

              --- Process leading to microvesicles in squamous epithelium

                       --- Hydropic degeneration

                              ---> Coalescence of degenerative cells

                                       ---> Microvesicles

              --- Results and effects

                      --- A clue to the diagnosis of specific disease

                      --- Progressing to cell lysis

2. Degeneration involving fat

    1)  Fatty change [A Video]
          --- Formerly called fatty degeneration frequently
 

          --- Abnormal accumulation of lipid in the cytoplasm of parenchymal cell

                   <--- Mainly triglycerides

        (1) Occurrence

               --- Mainly liver cell, renal tubular epithelial cell or myocardial cells

        (2) Gross findings of fatty liver [A Video]

               --- Enlarged
                       --- Liver in severe case
  

                    Uniform yellow

               --- Greasy texture on the cut surface
 

               --- Periacinar pattern

                       --- Pale or yellow + Normal brown

                            (central vein)     (portal triad)

                       --- " Fatty cysts "

                               <--- Fatty change involved in many lobules  

        (3) Microscopic appearance

               --- Large, clear droplets

                        <--- Slowly progressing toxic condition or viral disease

                    Many, small droplets

                       <--- Foamy appearance

                                 --- Acute metabolic disease

                                 --- Accompanied by acute cellular swelling

               --- Free droplets

                        --- Choline deficiency or alcoholism

                    Membrane-bound droplets

                        --- Excessive fat intake

               --- Eccentrically placed nucleus due to the lipid droplets

                        --- Adipose tissue-like appearance

               --- Differentiation

                        --- Hydropic degeneration/ Glycogen/ Postmortem change

                        --- Special staining for lipid

                                 --- Myocardium/ Kidney(cat)

                                 --- Sudan III/ Osmic acid/ Nile blue    

        (4) Pathogenesis

            a. Excessive release of FFA

                 --- Intestine or adipose tissue

                         --- Overloading to hepatocytes

                 --- Ketosis or diabetes

            b. Decreased utilization or oxidation of FA

                 --- Chronic hypoxia

                      Chronic metabolic diseases

                       ===> Dysfunction of enzymes

                 --- Interference of activation of FA by CoA

                         <--- Mitochondrial damage

                                    ---> Decreased oxidation of FA

                                               ---> Accumulation of triglycerides

                                           Inhibition of FA influx

            c. Lipotrope deficiency

                 --- Methionine/ Choline deficiency
 

                 --- Diglycerides + Methionine or Choline on ER

                       ---> Increased systhesis of phospholipids (lipoproteins)

                 --- Under their deficiency

                       --- Prefered esterification of diglycerides into triglycerides

            d. FAs preferntially esterified to triglycerides

                 --- Acute ethanol poisoning
 

            e. Failure of protein synthesis

                 --- Poisoning

                      --- Alcohol/ Ethionine/ CCl₄/ Puromycin/ Phosphorus

                 --- Malnutrition                    

        (5) Results and effects

               --- Reversible degeneration

               --- Non-specific degeneration

    2)  Fatty replacement or infiltration [A Video]

         --- Abnormal accumulation of lipid and adipose cells

                 --- Not an intracellular degeneration

                      Seem to be replacing some of the atrophied tissue

                           <--- Fatty replacement (a pathological term)

        (1) Occurrence

               --- Myocardial and skeletal muscles

                    Pancreas                     

        (2) Gross finding

               --- Pallor

                    Mottled appearance

        (3) Microscopic appearance

        (4) Pathogenesis

              --- Etiology ?
                      --- Often found along with obesity

              --- Steatosis

                      --- A form of fatty infiltration

                      --- Large areas of muscle

                               ---> A pale or mottled color

                                      Heavy muscle of the hind leg

                                      Loin and shoulder in cattle/ pigs

                      --- No evident clinical signs

    3) Extracellular accumulation of lipids

        --- Rupture of cells with severe faty change

                ---> Extracellularly releasing triglycerides or phospholipids
                         ---> Pooling
                                Phagocytosed by macrophages
                                  ===> Making them visible
 

        (1) Chloestrol clefts
               --- Hemorrhage
 

        (2) Fat emboli [A Video]
               --- Traumatically injured adipose tissue
                    Bone marrow injured by bone fractures

        (3) Fatty casts in renal tubular lumen

               --- Renal tubular epithelium with fatty change

    4) Fatty degeneration of myelin
         --- Stainable fat produced as  a product of degeneration

3. Glycogen deposition
        --- Formerly dealt separately in 'glycogen infiltration' and 'glycogen storage diseases'
        --- Pathological, excessive accumulation of glycogen
 

        (1) Occurrence

               --- Epithelial cells

                     --- Renal tubules/ Liver cells

               --- Leukocytes/ Cardiac muscle

               --- Less often, smooth muscle/ Spleen/ Lymph node/ Brain

        (2) Grossly not detectable

        (3) Microscopic appearance

               --- Clear vacuoles or spaces in the cytoplasm

                        --- Differentiating points with fatty change/ hydropic degeneration

                                 --- Not necessarily round and sharp in outline

                                 --- Very clear,  irregularly shaped space in ordinary section 
                                 --- Not displacing the nucleus to the periphery

                                       # Steroid-induced hepatopathy in dogs
 

               --- E.M.

                        --- Distributed as beta or alpha particles

                             Beta particles

                                  --- Roughly isodiametric, slightly irregular particles
                                  --- 150-300 Å in diameter

               --- Alcohol fixation and alcohol staining

                        --- Best's carmine stain (Bright pink)

                             PAS

        (4) Pathogenesis

            a. Hyperglycemia, as in diabetes mellitus
                Hyperadrenocorticism
                Dogs received by corticosteroid (steroid-induced hepatopathy)

            b. Dying cells

                  ---> Intercellular release of glucose

                             ---> Absorption by leukocytes or renal cells

                                    Excretion into urine

                                        --- Proximal tubular epithelial reabsorption

            c. Well-nourished animals [Fig. 1] [Fig. 2]

                  --- Hepatic epithelium

                           <--- A finely foamy appearance

            d. Glycogen storage diseases (glycogenoses) [A Video]
                 --- Genetic defects in the enzymes involved in the metabolism and catabolism of glycogen
                        --- Autosomal recessive inherited disorders
                        --- At least 8  types of glycogen storage diseases in human (I-VIII)

                        --- Four of the 8 types in animals
                     

                a) Type II glycogenosis (Pompe's disease)

                       --- Deficiency of alpha-1, 4-glucosidase (lysosomal acid maltase)

                               --- Brain/ Muscle/ Liver
 

                               --- Probably storaged within lysosomes of most cells of the body
                                      --- ie, membrane-bounded
                                             <--- A type of lysosomal storage disorder

                b) Type III glycogenosis (Cori's disease)

                       --- A deficiency of the glycogen debranching enzymes

                               --- Amylo-1,6-glucosidase

                               --- Storaged diffusely throughout the cytosol of cytoplasm
 

                               --- Hepatocytes
                                    Myocardium/ Skeletal muscle/ Neurons

                       --- Grossly enlarged liver ie, hepatomegaly with hypoglycemia

                c) Type IV glycogenosis
                       --- Recently described

                       --- A deficiency of glycogen branching enzyme
                                --- Storage of abnormal glycogen in many tissues

                                        --- Particularly in skeletal and cardiac muscle   

                       --- Progressive skeletal and cardiac muscle degeneration and atrophy and then death   

                d) Type VII glycogenosis
                      --- A deficiency of the M (muscle) type of phosphofructokinase (PFK)

                      --- English springerspaniel dogs

                           A persistent compensated hemolytic anemia and episodes of intravascular hemolysis
                           with hemoglobinurea

                           Exercise intolerance/ Muscle wasting/ Rarely muscle cramping

                      --- Muscle glycogen concentration being approximately twice normal level

                           Microscopically affected muscle fibres
                              --- Paler staining than normal fibres

                              --- Containing deposits of a PAS staining amylopectin-like polysaccharide just beneath
                                   the sarcoplasm

        (6) Significance

              --- Not in itself injurious

              --- Indication of other injury 
          

4. Lysosomal storage diseases  [A Video 1/ A Video 2]

         --- A group of inherited disorders (about three dozen disorders)
                 --- Mostly autosomal recessive
 

                 --- Abnormal accumulation of catabolites in lysosomes of the cell

                         --- a. Mucopolysacharides                                
                              b. Sphingolipids (glycolipids)

                              c. Phospholipids/ Glycoproteins/ Glycogen/ Mucolipids

         --- Nearly complete or partial deficiencies of various catabolic hydrolytic enzymes
                  --- Currently 8 different mechanisms involved
                          --- Mostly from mutation of the gene coding for  specific hydrolase

         --- Occurrence

                --- Mucopolysacchridoses

                         --- Liver/ spleen/ connective tissue including neurons

                      Lipodoses

                         --- Neurons

                --- Hypomyelinogenesis

                        <--- Defective myelin metabolism

                --- A few case in animals

        A. Mucopolysaccharidoses (MPS)

              ---  Accumulation of glycoprotein (Mucoprotein, No uronic acid)

             (1) Occurrence

                a. Mucopolysaccharide-synthesizing cells
                      --- Cells that actively participate in recycling extracellular matrix are most severely
                           affected
 

                      --- Fibroblasts/ Endothelial cells/ Leukocytes

                           Chondrocytes/ Osteocytes

                b. Other cells which take up but is incapable of catabolizing mucopolysaccharides

                      --- Hepatocytes/ Renal tubular epithelium/ Reticuloendothelial cells

                c. Nerve cells

                     --- No catabolism of glycolipids

             (2) Types of MPS
                     --- MPS -I, MPS-III, MPS-VI, MPS-III

             (2) Microscopic appearance

                     --- A foamy appearanced microscopically

                             <--- Weak basophilicity

                                     Severe swelling of cell

                         # Mucoploysaccharide

                              --- Water-soluble

                              --- Alcohol fixation

                                       --- Alcian blue

                                            Toluidine blue --- Metachromatic

                             Neuronal glycolipids

                             --- Frozen section

                                     --- Alcian blue/ PAS/ Sudan III

                                          Metachromatic with toluidine blue

             (3) Pathogenecity

                   --- Deficiency of one or more enzymes necessary for catabolism of mucopolysaccharides

                          ---> Incomplete degradation of intracytoplasmic glycosaminoglycans

             (4) Significance

                   --- Cellular dysfunction

                        Arrest of endochondral bone growth

                           ---> Skelaetal deformities

        B. Sphingolipidoses (lipid storage diseases)                     
              --- Glycolipids
             
              --- A group of disorders caused by deficient activity of lysosomal hydrolases, which are involved
                   in the degradation of lipids that containing sphingosine as the basic molecular unit

        C. Lipodoses

              --- Lipid storage disease

                      ---> Displacement of Nissle substance with lipid vacuoles in nerons

                                --- Congenital metabolic disorder

                                        <--- Missing of key enzyme

            (1) Occurrence

                   --- Neuron

            (2) Microscopic appearance

                   --- Formation of clear or cloudy vacuoles in the cytoplasm of parenchymal cells

            (3) Pathogenesis

                  Absence of key enzyme (beta-galactosidase) for fat metabolism

                    ---> Disturbance of lipid metabolism

                              ---> Accumulation or deposits

                                        --- Gangliosides or sphingomyelin (<-- Matrix in nerve tissue or brain)

        D. Glycoprotein storage diseases
              --- Oligosacccharides as the major storage compounds
              --- Deficient activity of enzymes that participate in the degradation o oligosaccharides
              
        E. Glycogen storage diseases
              --- Type II (Pompe's disease)

        F. Mucolipidoses
 

5. Drug-induced lysosomal storage disease
    --- Inhibition of iduronate sulfatase and beta-glucuronidase
            --- Mucopolysaccharidosis
            --- Suramin (a trypanocidal and antifilarial drug)

     --- Inhibition of phospholipase A1 and A2
            --- Phospholipidosis
            --- Amiodarone (an antiarryhthmic drug)

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