Types of necrosis

Depending on the type of tissue involved and the nature of the injurious agents there are different types of necrosis could be identified.

There are two main types of necrosis, coagulative necrosis and liquefactive necrosis. Also there are four other special types of necrosis which includes, fat necrosis, caseous necrosis, fibrinoid necrosis and gangrene.

Coagulative necrosis
Coagulative necrosis is a form of necrosis in which the components of the cells are necrosed but the cells retain its cellular outline or architecture often for several days. But the nucleus disappears. Under light microscope coagulative necrosis is seen as eosinophilic cell shadows without nuclei. In some cells pyknotic and karyorrhectic nuclei may be seen.Coagulative necrosis is commonly seen in solid organs like heart, kidney, liver and adrenals and the affected tissues become firm in texture. Typically the injurious agent is hypoxia. For example myocardial infarction, renal infarction. Other causes of coagulative necrosis are coagulative necrosis of the liver in viral hepatitis,coagulative necrosis of skin in burns.

Mechanism of coagulative necrosis
Injurious agents like hypoxia(due to increased intracellular acidity) and heat denature the intracellular proteins, including the lysosomal enzymes. This prevents cell being autolysed and the structural outline persist. Later the enzymatic activity of inflammatory cells digests these cells. This process Is called heterolysis.

Macroscopy of coagulative necrosis
Initial several hours the necrotic areas may appear normal. Then the area show a mottled appearance due to seepage of blood into the necrotic area from damaged blood vessels. Later blood gets cleared out and the necrotic area appears pale. A few days later necrosis area become firm and usually pale. This is the typical appearance of coagulative necrosis. However, sometimes the necrotic focus could look like hemorrhagic. For example necrosis occurring in already congested tissues like in testis undergone torsion and in tissues with dual blood supply like in lung infarction.

Microscopy of coagulative necrosis
Microscopic appearance depends on the time since onset of cell death. Nuclear changes described above are typically seen in coagulative necrosis. After 1-2 days cellular outlines with eosinophilic homogenous appearance is seen without a nucleus. There will be associated inflammation.
Caseous necrosis

Caseous necrosis is a type of coagulative necrosis characterized by yellowish crumbling nature of necrotic tissues and it is Like cottage cheese. The caseous necrosis typically occurs in infection by Mycobacterium tuberculosis and sometimes in fungal infections.

Liquefactive necrosis
In liquefactive necrosis, necrotic cells undergo rapid lysis or liquefaction due to the lysosomal enzymes released from necrotic cells and this is called autolysis. The typical example in liquefactive necrosis of brain following ischemia (brain infection). This may be due to high content of proteolytic enzymes in brain cells. Another example of liquefactive necrosis is suppuration. Here the liquefaction is due to proteolytic enzymes released by the neutrophils and this is called heretolysis.

Fibrinoid necrosis
Fibrinoid necrosis occur in connective tissues characterized by deposition of homogeneous bright pink (hyaline) material in necrotic foci. This material contains various amounts of immunoglobulins, compliments and breakdown products of fibrin and collagen.

Situations where fibrinoid necrosis is seen:

• Walls of arteries in vasculitis and malignant hypertension (especially in arterioles).
• In rheumatic carditis in Aschoff bodies.

Clinical manifestations:
In small vessel vasculitis, fibrinoid necrosis of vessel wall leads to red cell extravasation. (Eg. Palpable purpura in skin). In rheumatic carditis, fibrinoid necrosis manifest as Aschoff bodies. They heal by fibrosis. Fibrous distortion of the cardiac valve cusps leads to valvular abnormalities like stenosis and incompetent. Glomeruli may affect in some types of glomerulonephritis.

Apoptosis and necrosis

When cells are stressed so severely, exposed to inherently damaging agents or suffer from intrinsic abnormality, the cells are no longer able to survive. Such injurious stimuli affects several metabolic pathways and many cellular organelles. Initially the injury may progress through a reversible stage to an irreversible stage.

Reversible cell injury
This is the early stage or mild form of injury. If the injurious agent is removed, the functional and morphological changes can be reversed. Because the injurious agents do not cause membrane damage.

Irreversible cell injury or cell death
With continuous damage to the cell, the injury becomes irreversible, the cell can not servieve and it dies. There are two types of cell deaths.

• Necrosis
• Apoptosis

Necrosis
When damage to the cell membrane and membranes of the organelles due to the injurious agent, enzymes leak out from the lysosomes and digest the cellular content resulting in necrosis. Also there is a inflammation in the surrounding viable tissues due to leak out of cellular content.

Common causes of necrosis

• IschemiaToxins
• Infections
• Trauma

Nuclear changes after cell death
Chromatin clumps together, therefore nuclear become shrunken, dense and darkly staining. These nuclear changes are called pyknosis. Pyknotic nucleus breaks up into small particles known as karyorrhexis. The lysosomal enzymes such as deoxyribonucleases act on these nuclear particles and lyse them and this is called karyolysis.

In rapidly occurring necrosis and in necrosis of issues with high lysosomal enzyme activity, nuclear lysis can occur without a recognizable pyknotic stage (E.g: in liquefactive necrosis).

Cytoplasmic changes after cell death
With light microscopy, cytoplasmic changes are the cellular changes detectable first in necrosis. The cytoplasm becomes deeply eosinophilic and homogeneous due to protein denaturation and loss of ribosomes (ribosomes give a basophilic tinge to the cytoplasm). Later disruption of cellular organelles leads to vacuolization of the cytoplasm. Eventually there will be a complete digestion of cellular elements by cell's own lysosomal enzymes. This is called autolysis.

Autolysis is rapid in tissues rich in hydrolytic enzymes such as pancreas, gastric mucosa. Intermediate in tissues like heart, liver and kidney, delayed in tissues containing little such enzymes like fibrous tissue. The lysosomal enzymes secreted by inflammatory cells like neutrophils in the surrounding viable tissue also aid digestion of the necrotic cells and this is called heterolysis.

Postmortem autolysis is diffuse (but starts early in organs is like pancreas) and not associated with inflammation. In necrosis, release of intracellular components initiates an inflammatory response in the surrounding viable tissues.

Apoptosis
Apoptosis is a mechanism by which cells die by activation of an inbuilt death program which is also known as programmed cell death. This is a way of cells committing suicide. This is an important mechanism by which body gets rid of unwanted cells such as aged cells, nonfunctional cells, cells with undesired actions and cells with genetic damages.

A few examples where apoptosis takes place under normal or physiological circumstances:

• During embryogenesis - shaping of organs and body parts. For example formation of fingers and toes of the fetus requires the removal, by apoptosis, of the tissues between them.
• In germinal centers of lymphoid follicles unwanted transformed immune cells are deleted by apoptosis.
• Hormone induced cell atrophy - involution of mammary tissue after cessation of breast-feeding and after menopause.
• The sloughing off of the inner lining of the uterus (the endometrium) at the start of menstruation occurs by apoptosis.
• Getting rid of cells with genetic damage and cells with harmful spontaneous mutations during the cell division.

Inappropriate apoptosis is responsible for many disease conditions.

Mechanism of apoptosis
Every cell in the body has an inbuilt death program. This program is tightly regulated and is in an inhibited state under the normal circumstances. Once this program is activated it leads to activation of cascade of events eventually leading to death of the cell.

Morphological changes during apoptosis
Initially the cytoplasm becomes deeply eosinophilic and cell becomes round or oval shaped. The organelles tightly packed together. Chromatin condensation can be seen in the nucleus. These changes leads to cell shrinkage. Then the cytoskeleton degenerates and nuclear fragmentation can be seen. The cell forms membrane bound buds which contain cytoplasm, organelles and nuclear fragments and the process called budding. These buds get pinched off from the cell and get engulfed by the neighboring cells or macrophages and degraded within phagolysosomes of these cells.

Apoptosis vs necrosis
Throughout the process of apoptosis the cell membrane is intact and there is no leakage of cellular contents to the surrounding viable tissues. Therefore there is no accompanying inflammation in apoptosis. Therefore apoptosis is a silent process with no or minimal secondary consequences in normal physiological state. This is an energy dependent process. Whereas in necrosis there is cellular swelling and disintegration of cell membrane leading to leakage of cellular contents out of the cell which triggers inflammatory response in adjacent viable tissues. Necrosis is not an energy dependent process. Necrosis is always a pathological event and do not occur in normal health.

In lymph nodes macrophages that engulf and digest apoptotic cells are called tingible body macrophages and are frequently found within the reactivate germinal centers of lymphoid follicles. The tingible bodies are the bits of nuclear debris from the apoptotic cells.

Blount's disease

Blount's disease affects the inner edge of the upper shin bone (tibia) at the knee growth plate (epiphyseal growth plate runs horizontally across the knee), causing it to decrease its of growth in the portion of the growth plate is closest to the leg's inseam. The outside part of the growth plate continues to grow normally, leading to progressive bowing. Blount's disease affects two different age groups. There is:

• Infantile Blount's, seen in young children, and
• Adolescent Blount's seen in teenagers.

In both groups, the children tend to be overweight for their age. This bowing deformity is always associated with internal tibial torsion (an inward direction of the ankle and foot relative to the direction of the knee).

If infantile Blount's disease is diagnosed early enough, bracing can be instituted. We have had good results bracing children as young as two years old. Usually by the age of three, treatment will require a tibial osteotomy to straighten the lower extremity. Many will wait and see how it goes and let the most effective bracing period go right by. In a special parallax free three exposure x-ray of the full leg from hip to ankle, with the knee carefully aimed straight ahead, a line through hip and ankle centers ought to pass through knee center. If that line passes outside the bone of the knee, then the angulation will worsen with time and not self correct. We have seen no such reversals in that subset of children. We prefer to brace as bracing early not only works better but heads off the addition damage to the inner growth plate caused by the angular mechanical compression caused by the bowed leg.

Depending on how crushed the growth plate is, the bowing may recur after surgery. Tibial osteotomy is also part of the treatment for the adolescent. There are many different techniques for performing the osteotomy. No matter what technique is chosen, the osteotomy must correct the bowing and twist at the same time. Bracing also attempts to correct both deformities at the same time. X-rays are helpful for diagnosing Blount's disease as well. But there is an important detail to be aware of when taking these x-rays. Usually an anterior -posterior view of the lower extremity is obtained with the knee pointed straight ahead (ignoring the foot direction). The growth plates are checked for any abnormality, such as is seen in Rickets and other diseases. Angle measurements about the proximal tibia as well as between the tibia and femur are made, which will help determine if her Blount's disease is present. Importantly a line from the center of the hip joint to the center of the ankle joint is drawn as discussed above. This is the best prognosticator for progression.

This line is the weight bearing line of the lower extremity. If it passes completely beyond the knee joint substance, then whenever weight is placed on the leg it is passed from the hip to the ankle levered through the very medial part of the knee. The leverage amplifies the forces. This will tend to make the bowing worse over time, damaging the growth plate and is an indication for treatment of the bowing.