Reversible Cell Injury, Mechanism and Morphology

 REVERSIBLE CELL INJURY, MECHANISM AND MORPHOLOGY

REVERSIBLE CELL INJURY: If the ischaemia or hypoxia is of short duration, the effects may be reversible on rapid restoration of circulation e.g. in coronary artery occlusion, myocardial contractility, metabolism and ultra structure are reversed if the circulation is quickly restored. Th e sequential biochemical and ultra structural changes in reversible cell injury are as under:

1. Decreased generation of cellular ATP: Damage by ischaemia from interruption versus hypoxia from other causes. All living cells require continuous supply of oxygen to produce ATP which is essentially required for a variety of cellular functions (e.g. membrane trans port, protein synthesis, lipid synthesis and phospholipid metabolism). ATP in human cell is derived from 2 sources:

a) Firstly, by aerobic respiration or oxidative phosphorylation (which requires oxygen) in the mitochondria.

b) Secondly, cells may subsequently switch over to anaerobic glycolytic oxidation to maintain constant supply of ATP (in which ATP is genera ted from glucose/glycogen in the absence of oxygen). Ischaemia due to interruption in blood supply as well as hypoxia from other causes limit the supply of oxygen to the cells, thus causing decreased ATP generation from ADP:

● In ischaemia from interruption of blood supply, aerobic respiration as well as glucose availability are both compromised resulting in more severe and faster effects of cell injury. Ischaemic cell injury also causes accumulation of metabolic waste products in the cells. 

 2. Intracellular lactic acidosis: Nuclear clumping Due to low oxygen supply to the cell, aerobic respiration by mitochondria fails first. Th is is followed by switch to anaerobic glycolytic pathway for the requirement of energy (i.e. ATP). This results in rapid depletion of glycogen and accumulation of lactic acid lowering the intracellular pH. Early fall in intracellular pH (i.e. intracellular lactic acidosis) results in clumping of nuclear chromatin. 

3. Damage to plasma membrane pumps: Hydropic swelling and other membrane changes Lack of ATP interferes in generation of phospholipids from the cellular fatty acids which are required for continuous repair of membranes. This results in damage to membrane pumps operating for regulation of sodium-potassium and calcium as under:

i) Failure of sodium-potassium pump . 

ii) Failure of calcium pump 

 4. Reduced protein synthesis: Dispersed ribosomes As a result of continued hypoxia, membranes of endoplasmic reticulum and Golgi apparatus swell up. Ribosomes are detached from granular (rough) endoplasmic reticulum and polysomes are degraded to monosomes, thus dispersing ribosomes in the cytoplasm and inactivating their function. Similar reduced protein synthesis occurs in Golgi apparatus. Ultrastructural evidence of reversible cell membrane damage is seen in the form of loss of microvilli, intramembranous particles and focal projections of the cytoplasm (blebs). Myelin figures may be seen lying in the cytoplasm or present outside the cell; these are derived from membranes (plasma or organellar) enclosing water and dissociated lipoproteins between the lamellae of injured membranes. Up to this point, withdrawal of acute stress that resulted in reversible cell injury can restore the cell to normal state.

MORPHOLOGY OF REVERSIBLE CELL INJURY 

 A. Hydropic change

 B. Hyaline change

 C. Mucoid change

 D. Fatty change

 A. HYDROPIC CHANGE: Hydropic change means accumulation of water within the cytoplasm of the cell. Other synonyms used are cloudy swelling (for gross appearance of the affected organ) and vacuolar degeneration (due to cytoplasmic vacuolation). Hydropic swelling is an entirely reversible change upon removal of the injurious agent. 

                                                               HYDROPIC CHANGE

ETIOLOGY: This is the commonest and earliest form of cell injury from almost all causes. Th e common causes include acute and sub acute cell injury from various etiologic agents such as bacterial toxins, chemicals, poisons, burns, high fever, intravenous administration of hypertonic glucose or saline etc. 

PATHOGENESIS: Cloudy swelling results from impaired regulation of sodium and potassium at the level of cell membrane. Th is results in intracellular accumulation of sodium and escape of potassium. Th is, in turn, is accompanied with rapid fl ow of water into the cell to maintain iso-osmotic

B. HYALINE CHANGE: T he word ‘hyaline’ means glassy (hyalos = glass). Hyalinisation is a common descriptive histologic term for glassy, homogeneous, eosinophilic appearance of proteinaceous material in haematoxylin and eosin-stained sections and does not refer to any specific substance. Though fibrin and amyloid have hyaline appearance, they have distinctive features and staining reactions and can be distinguished from non-specific hyaline material. Hyaline change is seen in heterogeneous pathologic conditions and may be intracellular or extracellular.

                                                 HYALINE CHANGE (GLOMERULUS)

INTRACELLULAR HYALINE: Intracellular hyaline is mainly seen in epithelial cells. A few examples are as follows: 

1. Hyaline droplets in the proximal tubular epithelial cells due to excessive reabsorption of plasma proteins in proteinuria.

 2. Hyaline degeneration of rectus abdominalis muscle called Zenker’s degeneration, occurring in typhoid fever. The muscle loses its fibrillar staining and becomes glassy and hyaline. 

 EXTRACELLULAR HYALINE Extracellular hyaline commonly termed hyalinisation is seen in connective tissues. A few examples of extracellular hyaline change are as under:

1. Hyaline degeneration in leiomyomas of the uterus  

2. Hyalinised old scar of fibrocollagenous tissues 

3. Hyaline arteriolosclerosis in renal vessels in hyper tension and diabetes mellitus.

C. MUCOID CHANGE: Mucoid means mucus-like. Mucus is the secretory product of mucous glands and is a combination of proteins complexed with mucopolysaccharides. Mucin, a glycoprotein, is its chief constituent. Mucin is normally produced by epithelial cells of mucous membranes and mucous glands, as well as by some connective tissues such as ground substance in the umbilical cord. By convention, connective tissue mucin is termed myxoid. Both epithelial and connective tissue mucin are stained by alcian blue. 

                                                   MUCOID CHANGE (SYNOVITIS)

 EPITHELIAL MUCIN Following are some examples of functional excess of epithelial mucin: 

1. Catarrhal inflammation of mucous membrane (e.g. of respiratory tract, alimentary tract, uterus). 

2. Obstruction of duct leading to mucocele in the oral cavity and gallbladder. 

CONNECTIVE TISSUE MUCIN A few examples of disturbances of connective tissue mucin or myxoid change are as under:

1. Mucoid or myxoid change in some tumours e.g. myxomas, neurofibromas, fibroadenoma, soft tissue sarcomas etc  

2. Dissecting aneurysm of the aorta due to Erdheim’s medial degeneration and Marfan’s syndrome.

D. FATTY CHANGE: Steatosis or fatty metamorphosis is the intracellular accumulation of neutral fat within parenchymal cells. It includes the older, now abandoned, terms of fatty degeneration and fatty infiltration because fatty change neither necessarily involves degeneration nor an infiltration. The deposit is in the cytosol and represents an absolute increase in the intra cellular lipids. Fatty change is particularly common in the liver but may occur in other non-fatty tissues as well e.g. in the heart, skeletal muscle, kidneys and other organs. Fatty Liver Liver is the commonest site for accumulation of fat because it plays central role in fat metabolism. Depending upon the cause and amount of accumulation, fatty change may be mild and reversible, or severe producing irreversible cell injury and cell death. 

                                                        FATTY CHANGE IN LIVER

ETIOLOGY: Fatty change in the liver may result from one of the two types of causes:

1. Conditions with excess fat: These are conditions in which the capacity of the liver to metabolise fat is exceeded e.g.

 i) Obesity 

ii) Diabetes mellitus 

iii) Congenital hyperlipidaemia 

2. Liver cell damage: These are conditions in which fat cannot be metabolised due to liver cell injury e.g. 

i) Alcoholic liver disease 

ii) Starvation 

iii) Protein calorie malnutrition 

iv) Acute fatty liver in late pregnancy 

v)  Hypoxia (e.g. anaemia, cardiac failure) 

vi) Chronic illnesses (e.g. tuberculosis)

vii) Hepatotoxins (e.g. carbon tetrachloride, chloroform, ether) 

viii) Drug-induced liver cell injury (e.g. administration of methotrexate